Triazole compounds with dopamine-D3-receptor affinity

ABSTRACT

Triazole compounds of the following formula                    
     where R 1 , R 2 , A and B have the meanings given in the description are described. The compounds according to the invention possess a high affinity for the dopamine D 3  receptor and can therefore be used for treating diseases which respond to the influence of dopamine D 3  ligands.

The invention relates to triazole compounds and to the use of these compounds. These compounds possess valuable therapeutic properties and can be used for treating diseases which respond to the influence of dopamine D₃ receptor ligands.

Compounds of the type which is under discussion here and which possess physiological activity are already known. Thus, WO 94/25013; 96/02520; 97/43262; 97/47602; 98/06699; 98/49145; 98/50363; 98/50364 and 98/51671 describe compounds which act on the dopamine receptors. DE 44 25 144 A, WO 96/30333, WO 97/25324, WO 97/40015, WO 97/47602, WO 97/17326, EP 887 350, EP 779 284 A and Bioorg. & Med. Chem. Letters 9 (1999) 2059-2064 disclose further compounds which possess activity as dopamine D₃ receptor ligands. U.S. Pat. Nos. 4,338,453; 4,408,049 and 4,577,020 disclose triazole compounds which possess antiallergic or antipsychotic activity. WO 93/08799 and WO 94/25013 describe compounds of the type which is under discussion here and which constitute endothelin receptor antagonists. Additional triazole compounds, which inhibit blood platelet aggregation and which have a hypotensive effect are described in Pharmazie 46 (1991), 109-112. Further triazole compounds which possess physiological activity are disclosed in EP 691 342, EP 556 119, WO 97/10210, WO 98/24791, WO 96/31512 and WO 92/20655.

Neurons obtain their information by way of G protein-coupled receptors, inter alia. There are a large number of substances which exert their effect by way of these receptors. One of them is dopamine.

A number of facts about the presence of dopamine, and its physiological function as a neuron transmitter, are known with certainty. Disturbances of the dopaminergic transmitter system result in diseases such as schizophrenia, depression and Parkinson's disease. These, and other, diseases are treated with drugs which interact with the dopamine receptors.

By 1990, two subtypes of dopamine receptor had been clearly defined pharmacologically, namely the D₁ and D₂ receptors.

More recently, a third subtype has been found, namely the D₃ receptor, which appears to mediate some of the effects of the antipsychotic and anti-Parkinson agents (J. C. Schwartz et al., The Dopamine D₃ Receptor as a Target for Antipsychotics, in Novel Antipsychotic Drugs, H. Y. Meltzer, Ed. Raven Press, New York 1992, pages 135-144; M. Dooley et al., Drugs and Aging 1998, 12, 495-514).

Since D₃ receptors are chiefly expressed in the limbic system, it is assumed that while a selective D₃ ligand would probably have the properties of known antipsychotic agents, it would not have their dopamine D₃ receptor-mediated neurological side-effects (P. Sokoloff et al., Localization and Function of the D₃ Dopamine Receptor, Arzneim. Forsch./Drug Res. 42(1), 224 (1992); P. Sokoloff et al. Molecular Cloning and Characterization of a Novel Dopamine Receptor (D₃) as a Target for Neuroleptics, Nature, 347, 146 (1990)).

Surprisingly, it has now been found that certain triazole compounds exhibit a high affinity for the dopamine D₃ receptor and a low affinity for the D₂ receptor. These compounds are consequently selective D₃ ligands.

The present invention relates, therefore, to the compounds of the formula I:

where

R¹ is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₃-C₆-cycloalkyl or phenyl;

R² is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COOR³, CONR³R⁴, NR³R⁴, SO₂R³, SO₂NR³R⁴, or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from O, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COR³, NR³R⁴, NO₂, SO₂R³, SO₂NR³R⁴ and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C₁-C₆-alkyl, C₁-C₆-alkoxy, NR³R⁴, CN, CF₃, CHF₂ or halogen;

R³ and R⁴ are, independently of each other, H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, or phenyl;

A is C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z which is selected from O, S, CONR³, COO, CO, C₃-C₆-cycloalkyl and a double or triple bond;

B is a radical of the following formula:

 where

X is CH₂ or CH₂CH₂;

R⁶, R⁷ and R⁸ are, independently of each other, selected from H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, which may be substituted by amino, mono- or di-C₁-C₄-alkylamino; C₁-C₆-alkylthio, halogen or phenyl; OH, C₁-C₆-alkoxy, OCF₃, OSO₂CF₃, SH, C₁-C₆-alkylthio, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, NO₂, CO₂R³, SO₂R³, SO₂NR³R⁴, where R³ and R⁴ have the abovementioned meanings and may also form together with the N atom to which they are bonded a saturated or unsaturated heterocycle with 5 to 7 ring atoms and 1 or 2 N and/or O heteroatoms, CONR³R⁴, NHSO₂R³, NR³R⁴, a 5- or 6-membered carbocyclic, aromatic or nonaromatic ring and a 5- or 6-membered heterocyclic, aromatic or nonaromatic ring with 1 or 2 heteroatoms which are selected, independently of each other, from O, N and S, with the carbocyclic or heterocyclic ring being able to have one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, phenyl, phenoxy, halogen, C₁-C₆-alkoxy, OH, NO₂, CF₃ and CHF₂, and with two of the substituents R⁶, R⁷ and R⁸ being able to form, together with the carbon atoms of the phenyl ring to which they are bonded, a phenyl, cyclopentyl or cyclohexyl ring which is fused to the phenyl ring with the possibility for one or two of the CH or CH₂ groups in the fused ring being replaced by a nitrogen atom, a NH or a N—(C₁-C₆-alkyl) group;

and the salts thereof with physiologically tolerated acids.

The compounds according to the invention are selective dopamine D₃ receptor ligands which act in the limbic system in a regioselective manner and which, as a result of their low affinity for the D₂ receptor, have fewer side-effects than do the classic neuroleptic agents, which are D₂ receptor antagonists. The compounds can therefore be used for treating diseases which respond to dopamine D₃ ligands, i.e. they are effective for treating those diseases in which affecting (modulating) the dopamine D₃ receptors leads to an improvement in the clinical picture or to the disease being cured. Examples of such diseases are diseases of the cardiovascular system and the kidneys, diseases of the central nervous system, in particular schizophrenia, affective disorders, neurotic stress and somatoform disorders, psychoses, Parkinsonism, attention deficit disorders, hyperactivity in children, epilepsy, amnesic and cognitive disorders such as learning and memory impairment (impaired cognitive function), anxiety states, dementia, delirium, personality disorders, sleep disturbances (for example restless legs syndrome), disorders of the sex life (male impotence), eating disorders and addictive disorders. Moreover they are useful in the treatment of stroke.

Addictive disorders include the psychological disorders and behavioral disturbances caused by the abuse of psychotropic substances such as pharmaceuticals or drugs, and other addictive disorders such as, for example, compulsive gambling (impulse control disorders not elsewhere classified). Addictive substances are, for example: opioids (for example morphine, heroin, codeine); cocaine; nicotine; alcohol; substances which interact with the GABA chloride channel complex, sedatives, hypnotics or tranquilizers, for example benzodiazepines; LSD; cannabinoids; psychomotor stimulants such as 3,4-methylenedioxy-N-methyl-amphetamine (ecstasy); amphetamine and amphetamine-like substances such as methylphenidate or other stimultants including caffeine. Addictive substances of particular concern are opioids, cocaine, amphetamine or amphetamine-like substances, nicotine and alcohol.

The compounds according to the invention are preferably used for treating affective disorders; neurotic, stress and somatoform disorders and psychoses, e.g. schizophrenia.

Within the context of the present invention, the following expressions have the meanings given in conjunction with them:

Alkyl (also in radicals such as alkoxy, alkylthio, alkylamino etc.) is a straight-chain or branched alkyl group having from 1 to 6 carbon atoms and, in particular from 1 to 4 carbon atoms. The alkyl group can have one or more substituents which are selected, independently of each other, from OH, OC₁-C₆-alkyl, halogen or phenyl. In the case of a halogen substituent, the alkyl group can, in particular, encompass, 1, 2, 3 or 4 halogen atoms which can be located on one or more C atoms, preferably in the α or ω position. CF₃, CHF₂, CF₂Cl or CH₂F are particularly preferred.

Examples of an alkyl group are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, etc.

Cycloalkyl is, in particular, C₃-C₆-cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Alkylene radicals are straight-chain or branched. If A does not have a group Z, A then comprises from 4 to 10 carbon atoms, preferably from 4 to 8 carbon atoms. The chain between the triazole nucleus and group B then has at least four carbon atoms. If A has at least one of said Z groups, A then comprises from 3 to 10 carbon atoms, preferably from 3 to 8 carbon atoms.

If the alkylene groups comprise at least one of the Z groups, this or these groups can then be arranged in the alkylene chain at an arbitrary site or in position 1 or 2 of the A group (seen from the triazole radical). The radicals CONR² and COO are preferably arranged such that the carbonyl group is in each case facing the triazole ring. Particular preference is given to the compounds of the formula I in which A is —Z—C₃-C₆-alkylene, in particular —Z—CH₂CH₂CH₂—, —Z—CH₂CH₂CH₂CH₂—, —Z—CH₂CH═CHCH₂—, —Z—CH₂C(CH₃)═CHCH₂—,

—Z—CH₂CH(CH₃)CH₂— or a linear —Z—C₇-C₁₀-alkylene radical, with Z being bonded to the triazole ring. Z is preferably CH₂, O and, in particular, S. Preference is additionally given to A being —(CH₂)₄—, —(CH₂)₅—, —CH₂CH₂CH═CHCH₂—,

—CH₂CH₂C(CH₃)═CHCH₂— or —CH₂CH₂CH(CH₃)CH₂—.

Halogen is F, Cl, Br or I, preferably F or Cl.

X is preferably —CH₂-CH₂—.

R¹ is preferably H, C₁-C₆-alkyl or C₃-C₆-cycloalkyl.

If R² is an aromatic radical, this radical is then preferably one of the following radicals:

where

R⁹ to R¹¹ are H or the abovementioned substituents of the aromatic radical,

R¹² is H, C₁-C₆-alkyl or phenyl, and T is N or CH.

If the phenyl radical is substituted, the substituents are preferably in the m position or the p position.

The aromatic radical is particularly preferably a group of the formula:

where R⁹, R¹⁰ and R¹² have the abovementioned meanings. The indicated phenyl, pyridine, thiazolyl and pyrrole radicals are particularly preferred.

The radicals R⁹ to R¹¹ are preferably H, C₁-C₆-alkyl, OR³, CN, phenyl, which may be substituted by C₁-C₆-alkyl, C₁-C₆-alkoxy or halogen, CF₃ and halogen, and are, in particular, H, C₁-C₆-alkyl, OR³ and halogen. In this context, R³ has the abovementioned meanings.

Particularly preferably, R² is H, C₁-C₆-alkyl, NR³R⁴ (R³ and R⁴ are, independently of each other, H or C₁-C₆-alkyl), phenyl or a 5-membered aromatic heterocyclic radical which has 1 or 2 heteroatoms which are independently selected from N, S and O. The heterocyclic radical is preferably a pyrrole radical or a pyridine radical.

A is preferably C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z which is selected from O, S, COO, CO, a double bond and cyclohexyl.

Preferably, at least one of the radicals R⁶, R⁷ and R⁸ is H.

The radicals R⁶, R⁷ and R⁸ are preferably, and independently of each other, selected from H, C₁-C₆-alkyl, OH, C₁-C₆-alkoxy, C₁-C₆-alkylthio-C₁-C₆-alkyl, halogen, CN, NO₂, SO₂R³, SO₂NR³R⁴ and CONR³R⁴. Particularly preferably, the fused phenyl group has one or two substituents, i.e. one or two of the radicals R⁶, R⁷ and R⁸ is/are C₁-C₆-alkyl, halogen, CN, NO₂, SO₂R³ and, in particular, SO₂NR³R⁴, where R³ and R⁴, together with the N atom to which they are attached, can also be a 5-, 6- or 7-membered heterocycle, which may contain one or two additional heteroatoms being selected from N, O or S besides the nitrogen atom and which may be substituted, e.g. pyrrolidine, piperidine, morpholine or azepine.

If one of the radicals R⁶, R⁷ and R⁸ is a 5- or 6-membered heterocyclic ring, this ring is then, for example, a pyrrolidine, piperidine, morpholine, pyridine, pyrimidine, triazine, pyrrole, thiophene or pyrazole radical, with a pyrrole, pyrrolidine, pyrazole or thienyl radical being preferred.

If one of the radicals R⁶, R⁷ and R⁸ is a carbocyclic radical, this radical is then, in particular, a phenyl, cyclopentyl or cyclohexyl radical.

Particular preference is given to the compounds of formula I where

R¹ is H, C₁-C₆-alkyl or phenyl,

R² is H, C₁-C₆-alkyl, phenyl, thienyl, furanyl, pyridyl, pyrrolyl, thiazolyl or pyrazinyl,

A is —SC₃-C₁₀-alkylene which can comprise a double bond, and

R⁶, R⁷ and R⁸ are selected from H, C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, SO₂NR³R⁴, CN, NO₂, CF₃, CONR³R⁴, CHF₂, OSO₂CF₃, OCF₃ and NHSO₂-C₁-C₆-alkyl.

In here X is especially CH₂CH₂.

The invention also encompasses the acid addition salts of the compounds of the formula I with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid or benzoic acid. Other acids which can be used are described in Fortschritte der Arzneimittelforschung [Advances in pharmaceutical research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basle and Stuttgart, 1966.

The compounds of the formula I can exhibit one or more centers of asymmetry. The invention therefore includes not only the racemates but also the relevant enantiomers and diastereomers. The respective tautomeric forms are also included in the invention.

The process for preparing the compounds of the formula I consist in

a) reacting a compound of the formula (II)

where Y¹ is a customary leaving group, such as Hal, alkylsulfonyloxy, arylsulfonyloxy, etc., with a compound of the formula (III)

HB  (III);

or

b) reacting a compound of the formula (IV)

where Z¹ is O or S, and A¹ is C₁-C₁₀-alkylene or a bond, with a compound of the formula (V)

Y¹—A²—B  (V)

where Y¹ has the abovementioned meaning and A² is C₂-C₁₀-alkylene, with A¹ and A² together having from 3 to 10 C atoms and A¹ and/or A² where appropriate comprising at least one group Z; or

c) reacting a compound of the formula (VI)

where Y¹ and A¹ have the abovementioned meanings, with a compound of the formula (VII)

H—Z¹—A—B  (VII)

where Z¹ has the abovementioned meanings; or

d) reversing the polarity of a compound of the formula (VIII)

 using reagents which are known from the literature, such as 1,3-propanedithiol, KCN/water, TMSCN (trimethylsilyl cyanide) or KCN/morpholine, as described, for example, in

Albright Tetrahedron, 1983, 39, 3207 or

D. Seebach Synthesis 1969, 17 und 1979, 19 or

H. Stetter Angew. Chem. Int. Ed. 1976, 15, 639 or

van Niel et al. Tetrahedron 1989, 45, 7643

Martin et al. Synthesis 1979, 633,

 to give the products (VIIIa) (using 1,3-propanedithiol by way of example)

 and then chain-elongating with compounds of the formula (IX)

Y¹—A³—B  (IX)

where Y¹ has the abovementioned meaning and A³ is C₃-C₉-alkylene which can contain a group Z,

 with compounds of the formula (Ia)

where Z² is CO or a methylene group, and Z² and A² have together from 4 to 10 C atoms, being obtained after deprotecting or reducing, or

e) reacting a compound of the formula (VIII) with a compound of the formula (X)

Y²—A—B  (X)

where Y² is a phosphorane or a phosphonic ester, in analogy with customary methods, as described, for example, in Houben Weyl “Handbuch der Organischen Chemie” [Textbook of Organic Chemistry], 4th Edition, Thieme Verlag Stuttgart, Volume V/1b p. 383 ff, or Vol. V/1c p. 575 ff, or

f) reacting a compound of the formula (XI)

where Q is H or OH, with a compound of the formula III under reductive conditions in analogy with methods known from the literature, for example as described in J. Org. Chem. 1986, 50, 1927; or WO 92/20655.

The process for preparing a compound of the formula I where A comprises the groups COO or CONR³ consists in reacting a compound of the formula (XII)

where Y³ is OH, OC₁-C₄-alkyl, Cl or, together with CO, an activated carboxyl group, and A⁴ is C₀-C₉-alkylene, with a compound of the formula (XIII)

B—A—Z³  (XIII)

where Z³ is OH or NHR³.

Compounds of the formula B—H can be prepared as described, for example, in

Synth. Commun. 1984, 14, 1221;

S. Smith et al., Bioorg. Med. Chem. Lett. 1998, 8, 2859;

WO 97/47602 or WO 920655, or

J. Med. Chem. 1987, 30, 2111 and 2208 and 1999, 42, 118.

The compounds of the formula (IV) type are either known or can be prepared using known methods, as described, for example, in A. R. Katritzky, C. W. Rees (ed.) “Comprehensive Heterocyclic Chemistry”, Pergamon Press, or “The Chemistry of Heterocyclic Compounds” J. Wiley & Sons Inc. NY and the literature which is cited therein, or in S. Kubota et al. Chem. Pharm. Bull. 1975, 23, 955 or Vosilevskii et al. Izv. Akad. Nauk. SSSR Ser. Khim. 1975, 23, 955.

In the above formulae, R¹, R², R⁶, R⁷, R⁸, A, B and X have the meanings given in connection with formula I.

The compounds according to the invention, and the starting materials and the intermediates, can also be prepared in analogy with the methods which are described in the patent publications which were mentioned at the outset.

The above-described reactions are generally effected in a solvent at temperatures of between room temperature and the boiling temperature of the solvent employed. Examples of solvents which can be used are esters, such as ethyl acetate, ethers, such as diethyl ether or tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, dimethoxyethane, toluene, xylene, acetonitrile, ketones, such as acetone or methyl ethyl ketone, or alcohols, such as ethanol or butanol.

If desired, the reactions can be carried out in the presence of an acid-binding agent. Suitable acid-binding agents are inorganic bases, such as sodium carbonate or potassium carbonate, or sodium hydrogencarbonate or potassium hydrogencarbonate, sodium methoxide, sodium ethoxide, sodium hydride, or organometallic compounds, such as butyl lithium or alkyl magnesium compounds, or organic bases, such as triethylamine or pyridine. The latter can also simultaneously serve as the solvent.

Process (f) is effected under reducing conditions, e.g. using sodium borohydride, sodium cyanoborohydride or triacetoxy borohydride, where appropriate in an acid medium or in the presence of a Lewis acid, such as zinc chloride, or by way of catalytic hydrogenation.

The crude product is isolated in a customary manner, for example by means of filtering, distilling off the solvent or extracting from the reaction mixture, etc. The resulting compounds can be purified in a customary manner, for example by recrystallization from a solvent, by chromatography or by converting into an acid addition compound.

The acid addition salts are prepared in a customary manner by mixing the free base with the corresponding acid, where appropriate in solution in an organic solvent, for example a lower alcohol, such as methanol, ethanol or propanol, an ether, such as methyl tert-butyl ether, a ketone, such as acetone or methyl ethyl ketone, or an ester, such as ethyl acetate.

For treating the abovementioned diseases, the compounds according to the invention are administered orally or parenterally (subcutaneously, intravenously, intramuscularly or intraperitoneally) in a customary manner. The administration can also be effected through the nasopharyngeal space using vapors or sprays.

The dosage depends on the age, condition and weight of the patient and on the type of administration. As a rule, the daily dose of active compound is from about 10 to 1000 mg per patient and day when administered orally and from about 1 to above 500 mg per patient and day when administered parenterally.

The invention also relates to pharmaceuticals which comprise the compounds according to the invention. In the customary pharmacological administration forms, these pharmaceuticals are present in solid or liquid form, for example as tablets, film tablets, capsules, powders, granules, sugar-coated tablets, suppositories, solutions or sprays. In this context, the active compounds can be worked up together with the customary pharmacological auxiliary substances, such as tablet binders, fillers, preservatives, tablet disintegrants, flow-regulating agents, plasticizers, wetting agents, dispersants, emulsifiers, solvents, retarding agents, antioxidants and/or propellent gases (cf. H. Sucker et al., Pharmazeutische Technologie, Thieme-Verlag, Stuttgart, 1978). The resulting administration forms normally comprise the active compound in a quantity of from 1 to 99% by weight.

The following examples serve to explain the invention without limiting it.

EXAMPLE 1 6,7-Dimethoxy-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline

1A Preparation of the Starting Materials 2-(3-Chloropropyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

7.2 g (37 mmol) of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline were heated together with 4.05 ml (40 mmol) of 1-bromo-3-chloropropane, 11.3 g (81 mmol) of potassium carbonate and 610 mg (40 mmol) of sodium iodide in 250 ml of acetonitrile with stirring at 70° C. for four hours. After the reaction was complete, the solvent was distilled off, and the residue was taken up in water and extracted with methylene chloride. The combined organic phases were dried and concentrated, and the crude product was purified by chromatography on silica gel (mobile phase: methylene chloride/methanol=9/1). 4.8 g (45% of theory) of a yellowish oil were obtained.

¹H-NMR (CDCl₃): δ=2.0 (m, 2H); 2.6-2.8 (m, 6H); 3.5 (s, 2H); 3.6 (t, 2H); 3.8 (2s, 6H); 6.5 (s, 1H); 5.6 (s, 1H). C₁₄H₂₀ClNO₂ (269).

1B Preparation of the Final Product

380 mg (1.7 mmol) of 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole were heated with 450 mg (1.7 mmol) of the chlorinated base 1A and 40 mg (1.7 mmol) of lithium hydroxide in 5 ml of DMF while stirring at 100° C. for five hours. Workup entailed addition of 50 ml of water, extraction several times with methyl tert-butyl ether, drying of the combined organic phases, evaporation and purification by chromatography on silica gel (mobile phase: methylene chloride/2-5% methanol).

Yield: 0.2 g (49% of theory); ¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.6 (m, 2H); 2.7 (m, 2H); 2.8 (m, 2H); 3.3 (t, 2H); 3.5 (m, 2H); 3.6 (s, 3H); 3.8 (2s, 6H); 6.3 (s, 1H); 6.5 (s, 1H); 7.5 (m, 3H); 7.8 (m, 2H).

The title compound was obtained by treatment with ethereal hydrochloric acid C₂₃H₂₈N₄O₂S×HCl Melting point: 180-183° C.

EXAMPLE 2 6-Methoxy-2-{3-[(4-methyl-5-pyrrol-2-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline

2A Preparation of the Starting Compound 2-(3-Chloropropyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline

The above substance was prepared using 6-methoxy-1,2,3,4-tetrahydroisoquinoline in a manner analogous to 1A.

¹H-NMR (CDCl₃): δ=2.0 (q, 2H); 2.5-2.6 (m, 4H); 2.9 (m, 2H); 3.5 (s, 2H); 3.6 (m, 2H); 3.8 (s, 3H); 6.6 (d, 1H); 6.7 (dd, 1H); 6.9 (d, 1H).

2B Preparation of the Final Product

Preparation took place in analogy to Example 1 by reacting the chlorinated base prepared in 2A with 3-mercapto-4-methyl-5-(2-pyrrolyl)-1,2,4(4H)-triazole.

Yield: 52% of theory. C₂₀H₂₅N₅OS (383.5); Melting point: 179-181° C.

EXAMPLE 3 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-6-methoxy-1,2,3,4-tetrahydroisoquinoline

3A Preparation of the Starting Material 3-(3-Chloropropylmercapto)-4-methyl-5-phenyl-1,2,4(4H)-triazole

A suspension of 2.6 g (16.5 mmol) of 1-bromo-3-chloropropane, 0.22 g (1.5 mmol) of sodium iodide, 2.7 g (15 mmol) of 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole and 2.1 g (15 mmol) of potassium carbonate in 70 ml of ethanol were heated to boiling for one hour. After filtration hot, the filtrate was concentrated, taken up in water and extracted with dichloromethane. The combined orgainc phases were dried, filtered and concentrated, and the residue was chromatographed (mobile phase: methylene chloride/2% methanol).

Yield: 1.35 g (34% of theory) of white solid; ¹H-NMR (CDCl₃): δ=2.3 (q, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 3.7 (t, 2H); 7.5-7.7 (m, 5H). C₁₂H₁₄ClN₃S (267.8); Melting point: 137-141° C.

3B Preparation of the Final Product

0.7 g (2.5 mmol) of Compound 3A described above was stirred with 0.6 g (2.5 mmol) of 6-methoxy-1,2,3,4-tetrahydroisoquinoline oxalic acid salt in the presence of 1.1 ml (7.5 mmol) of triethylamine and catalytic amounts of sodium iodide in 6 ml of butanol at 120° C. for four hours. After the reaction was complete it was worked up by extraction with water and methyl tert-butyl ether, drying over sodium sulfate and concentrating, and the crude product was chromatographed on silica gel (mobile phase: methylene chloride with 0-3% methanol). 110 mg of a white solid were isolated.

C₂₂H₂₆N₄OS (394.5) MS (m/z): 395 [M]⁺.

EXAMPLE 4 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

4A Preparation of N-Acetyl-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

21.1 g (77 mmol) of 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride (prepared as described in G. Grunewald et al. J. Med. Chem 1999, 42, 118-134) in 50 ml of THF were added dropwise to a solution of 6.0 g (70 mmol) of piperidine and 10.9 g (84 mmol) of diisopropylethylamine in 230 ml of THF, and the mixture was heated under reflux for two hours. After the reaction was complete, the solvent was removed in vacuo, the residue was taken up in dichloromethane/water and, after making alkaline with 10% strength sodium hydroxide solution and separating the phases, the organic phase was dried over sodium sulfate. The crude product remaining after filtration and removal of the solvent was purified by column chromatography on silica gel (mobile phase: methylene chloride with 3% methanol).

Yield: 18.6 g (57.6 mmol); 82%; Melting point:171-174° C.

4B 7-(Piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

The compound described above was heated to boiling with 50% concentrated hydrochloric acid for two hours. The product formed a white precipitate on cooling. The residue was isolated, washed with water, digested in diethyl ether and dried in vacuo.

Yield: 12.1 g (38.2 mmol) 56% of theory.

4C 2-(3-Chloropropyl)-7-(piperidin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

12.1 g (38.2 mmol) of 7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetra-hydroisoquinoline and 8.4 g (84 mmol) of triethylamine were dissolved in DMF at 40° C., 9.0 g (57.2 mmol) of 1-bromo-3-chloropropane were added dropwise, and the mixture was stirred at 50° C. for 7 h. For workup, the mixture was concentrated, and the residue was taken up in water and extracted with dichloromethane. Drying over sodium sulfate, filtration and removal of the solvent were followed by purification by chromatography (silica gel; mobile phase: methylene chloride with 3% methanol) to result in 11.7 g (323.7 mmol) of a yellowish oil.

Yield: 86% of theory.

4D Preparation of the Final Compound

10.0 g (28.0 mmol) of the chlorinated base 4C described above, 6.4 g (28 mmol) of 3-mercapto-4-methyl-5-phenyl-4H-1,2,4-triazole and 0.7 g (28.0 mmol) of lithium hydroxide were heated in 77 ml of DMF at 100° C. for three hours. After the reaction was complete, the solvent was removed, and the residue was mixed with water and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Chromatography of the crude product (silica gel; mobile phase: methylene chloride with 0-5% methanol) afforded 3.9 g (7.5 mmol) of a white solid.

Yield: 27% of theory; ¹H-NMR (CDCl₃): δ=1.4 (m, 2H); 1.7 (m, 4H); 2.1 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 6H); 3.35 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 7.2 (d, 1H); 7.4 (s, 1H); 7.5 (m, 4H); 7.7 (m, 2H). C₂₆H₃₃N₅O₂S₂ (511.7) MS (m/z): 512.3 [M+H]⁺; Melting point: 105-108° C.

EXAMPLE 5 2-[4-(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)butyl]-7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline Hydrochloride Preparation of the Starting Compound

5A N-Acetyl-7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

was obtained as described in Example 4A by reacting morpholine with 2-acetyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonyl chloride in the presence of diisopropylamine in THF and by heating with 50% concentrated hydrochloric acid and, after alkaline workup, converted into the corresponding 7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline.

C₁₃H₁₈N₂O₃S (282) MS (m/z): 283 [M+H]⁺.

5B 2-(3-Chloropropyl)-7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

1.2 g (4.4 mmol) of 7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetra-hydroisoquinoline and 1.0 g (10 mmol) of triethylamine were dissolved in DMF at 40° C., 1.1 g (6.6 mmol) of 1-bromo-3-chloropropane were added dropwise, and the mixture was stirred at 40° C. for 3 h. For workup, the mixture was concentrated, and the residue was taken up in water and extracted with methyl tert-butyl ether. Drying over sodium sulfate, filtration and removal of the solvent were followed by purification by chromatography (silica gel; mobile phase: methylene chloride with 2% methanol) to afford 0.7 g (2 mmol) of a pale oil.

Yield: 46% of theory. ¹H-NMR (CDCl₃): δ=2.0 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 6H); 3.6-3.8 (m, 8H); 7.3 (d, 1H); 7.4 (s, 1H); 7.5 (d, 1H). C₁₆H₂₃N₂O₃S (359).

Preparation of the Final Compound

280 mg (1 mmol) of 2-[4-methyl-5-phenyl-1,2,4-(4H)-triazol-3-yl]-1,3-dithiane (described in WO 9902503) were dissolved in 2.5 ml of dry THF and, at −70° C., with the addition of 0.15 g of sodium iodide, treated with 0.75 ml (1.2 mmol) of a 15% strength solution of butyllithium in n-hexane. After stirring at −70+ C. for 45 min, 0.37 g (1 mmol) of 2-[3-chloropropyl]-7-(morpholin-4-yl-sulfonyl)-1,2,3,4-tetrahydroisoquinoline 5B dissolved in THF was added dropwise. The mixture was then slowly warmed to room temperature and subsequently heated at 40° C. for 90 min in order to achieve complete conversion. Workup entailed addition to ice/water and extraction several times with methylene chloride. After drying and concentration, 0.5 g (82% of theory) of the substituted dithiane remained and was then hydrogenated with Raney nickel and hydrogen in tetrahydrofuran at 40° C. over the course of 3 hours. After removal of the catalyst, the residue was purified by chromatography (silica gel, methylene chloride with 5% methanol).

Yield: 120 mg (29% of theory); 1H-NMR (CDCl₃): δ=1.8 (m, 2H); 2.0 (q, 2H); 2.6 (m, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.0 (m, 6H); 3.6 (s, 3H); 3.7 (m, 6H); 7.2 (d, 1H); 7.4 (s, 1H); 7.5 (m, 4H); 7.7 (m, 2H).

The title compound was obtained by adding ethereal HCl C₂₆H₃₃N₅O₃S.HCl (531.6); Melting point: 87-89° C.

The following were obtained in an analogous way:

EXAMPLE 6 1-(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-4-(7-(piperidin-1-yl-sulfonyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)butan-1-one

C₂₇H₃₃N₅O₃S (507.7) MS: 508.3 [M+H]⁺.

EXAMPLE 7 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile

C₂₂H₂₃N₅S (389.5); Melting point: 116-118° C.

EXAMPLE 8 5-[2-(Diethylammonio)ethoxy]-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline Dihydrochloride

C₂₇H₃₇N₅OS.2HCl (552.6); Melting point: 110-112° C.

EXAMPLE 9 N-Benzyl-2-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

C₂₆H₃₀N₆O₂S₃ (554.8); Melting point: 67-70° C.

EXAMPLE 10 N-Benzyl-2-{3-[(4-methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

C₂₇H₃₀N₆O₂S₂.2HCl (607.6); Melting point: 81-84° C.

EXAMPLE 11 5-Methoxy-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline

C₂₂H₂₆N₄OS (394.5); Melting point: 73-75° C.

EXAMPLE 12 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-nitro-1,2,3,4-tetrahydroisoquinoline

C₂₁H₂₄ClN₅O₂S (446); Melting point: 190-192° C.

EXAMPLE 13 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.65 (t, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.7 (s, 2H); 7.0 (m, 1H); 7.2 (m, 3H); 7.5 (m, 3H); 7.7 (m, 2H). C₂₁H₂₄N₄S (365.5).

EXAMPLE 14 2-(3-{[4-Methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.55 (s, 3H); 2.7 (t, 2H); 2.75 (t, 2H); 2.9 (t, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.65 (s, 2H); 7.0 (m, 1H); 7.1 (m, 3H); 8.9 (s, 1H). C₁₉H₂₃N₅S₂ (386.5).

EXAMPLE 15 2-{3-[(4-Methyl-5-pyridinium-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline Dihydrochloride

C₂₀H₂₃N₅S.2HCl (438.4); Melting point: 87-89° C.

EXAMPLE 16 7-[(Dimethylamino)sulfonyl]-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.65 (m, 8H); 2.75 (t, 2H); 3.0 (t, 2H); 3.3 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 7.2 (d, 1H); 7.4-7.6 (m, 7H). C₂₃H₂₉N₅O₂S₂ (472.6).

EXAMPLE 17 7-[(Dimethylamino)sulfonyl]-2-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline

1H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.5 (s, 3H); 2.6-2.8 (m, 10H); 2.9 (m, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.7 (s, 2H); 7.2 (m, 1H); 7.5 (m, 2H); 8.9 (s, 1H). C₂₁H₂₈N₆O₂S₃ (493.7).

EXAMPLE 18 Methyl 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline-7-carboxylate Oxalate

C₂₃H₂₇N₄O₂S.C₂HO₄ (512.6); Melting point: 160-163° C.

EXAMPLE 20 2-(3-{[4-Methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=1.4 (m, 2H); 1.7 (m, 4H); 2.1 (q, 2H); 2.5 (s, 3H); 2.6 (t, 2H); 2.7 (t, 2H); 3.0 (m, 6H); 3.3 (t, 2H); 3.5 (s, 3H); 3.6 (s, 2H); 7.2 (d, 1H); 7.45 (s, 1H); 7.5 (d, 1H); 8.9 (s, 1H).

C₂₄H₃₂N₆O₂S₃ (532.8).

EXAMPLE 21 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.6 (t, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.35 (t, 2H); 3.5 (s, 3H); 3.6 (m, 2H); 7.2 (d, 1H); 7.4-7.7 (m, 10H); 7.9 (d, 2H). C₂₇H₂₈N₄O₂S₂ (504.7).

EXAMPLE 22 2-(3-{(4-Methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinolin-7-yl Phenylsulfone

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.5 (s, 3H); 2.7 (t, 2H); 2.8 (t, 2H); 2.95 (t, 2H); 3.4 (t, 2H); 3.5 (s, 3H); 3.65 (m, 2H); 7.2 (d, 1H); 7.4-7.7 (m, 5H); 7.9 (d, 2H); 8.9 (s, 1H). C₂₅H₂₉N₅O₂S₃ (525.7).

EXAMPLE 23 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(morpholin-4-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (t, 4H); 3.35 (t, 2H); 3.6 (s, 3H); 3.7 (m, 6H); 7.3 (m, 1H); 7.4-7.6 (m, 5H); 7.9 (d, 2H). C₂₅H₃₁N₅O₃S₂ (525.7).

EXAMPLE 24 2-[4-(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)butyl]-7-(phenylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

C₂₈H₃₀N₄O₂S (486.6).

EXAMPLE 25 2-{3-[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-N-phenyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

¹H-NMR (CDCl₃): δ=1.3 (m, NH); 2.1 (q, 2H); 2.6 (m, 4H); 2.8 (t, 2H); 3.3 (t, 2H); 3.6 (s, 3H); 3.7 (m, 6H); 7.3 (m, 1H); 7.4-7.6 (m, 5H); 7.9 (d, 2H). C₂₆H₂₈N₆O₂S₂ (520.7). Melting point: 58-61° C.

EXAMPLE 26 2-(3-{[4-Methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-N-phenyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.5 (s, 3H); 2.7 (m, 4H); 2.9 (m, 2H); 3.3 (t, 2H); 3.5 (s, 3H); 3.6 (s, 32H); 7.0-7.2 (m, 6H); 7.5(m, 2H); 8.9 (s, 1H). C₂₅H₂₈N₆O₂S₃ (540.7); Melting point: 77-81° C.

EXAMPLE 27 2-(3-{[5-(2,4-Dimethoxy)phenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-sulfanyl}propyl)-7-(methylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=2.2 (q, 2H); 2.9 (m, 2H); 3.0 (m, 2H); 3.05 (s, 3H); 3.1 (m, 2H); 3.3 (m, 5H); 3.7 (s, 3H); 3.85 (s, 3H); 3.9 (s, 2H); 6.5 (s, 1H); 6.65 (d, 1H); 7.25 (d, 1H); 7.3 (d, 1H); 7.7 (s, 1H); 7.8 (d, 1H). C₂₄H₃₀N₄O₄S₂ (502.7) MS: 503.5 [M+H]⁺.

EXAMPLE 28 6,7-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline

C₂₁H₂₂Cl₂N₄S (433.4); Melting point: 138-139° C.

EXAMPLE 29 7,8-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline Hydrochloride

1H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.7 (m, 4H); 2.9 (t, 2H); 3.3 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 6.95 (d, 1H); 7.2 (d, 1H); 7.5 (m, 3H); 7.7 (m, 2H), [free base].

Salt precipitation with ethereal HCl led to the title compound C₂₁H₂₂Cl₂N₄S.×HCl (469.9); Melting point: 109° C.

EXAMPLE 30 7-Cyano-2-[4-(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)butyl]-1,2,3,4-tetrahydroisoquinoline Hydrochloride

C₂₃H₂₅N₅.HCl(407.9); Melting point: 175° C.

EXAMPLE 31 2-{3-[(4-Methyl-5-thien-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline Hydrochloride

C₂₀H₂₁F₃N₄S₂.Cl×HCl (475); Melting point: 184-185° C.

EXAMPLE 32 1-{2-[3-({4-Methyl-5-[4-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}ethanone

¹H-NMR (CDCl₃): δ=2.15 (q, 2H); 2.4 (s, 3H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (t, 2H); 3.3 (t, 2H); 3.6 (s, 3H); 3.75 (s, 2H); 7.1 (d, 1H); 7.6-7.8 (m, 6H). C₂₄H₂₅F₃N₄OS (474.5).

The hydrochloride of the title compound was obtained by treatment with ethereal hydrochloric acid: Melting point: 183° C.

EXAMPLE 33 6,7-Dichloro-2-(3-{[4-methyl-5-(4-methylphenyl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline Hydrochloride

1H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.4 (s, 3H); 2.7 (m, 4H); 2.8 (t, 2H); 3.3 (t, 2H); 3.5 (s, 2H); 3.6 (s, 3H); 7.1 (s, 1H); 7.2 (s, 1H); 7.3 (d, 2H); 7.5 (d, 2H); [free base].

The title compound was obtained by treatment with ethereal hydrochloric acid C₂₂H₂₄Cl₂N₄S.HCl (483.9) Melting point: 207-210° C.

EXAMPLE 34 6-Chloro-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline Hydrochloride

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.4 (s, 3H); 2.7 (m, 4H); 2.8 (t, 2H); 3.3 (t, 2H); 3.5 (s, 2H); 3.6 (m, 5H); 6.9 (d, 1H); 7.1 (m, 2H); 7.5 (d, 3H); 7.5 (d, 2H); [free base].

Salt precipitation with ethereal HCl led to the title compound C₂₁H₂₃ClN₄S.HCl (435.4); Melting point: 188-191° C.

EXAMPLE 35 2-(3-{[4-Methyl-5-(1-methyl-1H-pyrrol-2-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=1.4 (m, 2H); 1.7 (m, 4H); 2.1 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 6H); 3.35 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 3.9 (s, 3H); 6.2 (m, 1H); 6.4 (m, 1H); 6.8 (m, 1H); 7.2 (d, 1H); 7.4 (s, 1H); 7.5 (m, 2H). C₂₅H₃₄N₆O₂S₂ (514.7); Melting point: 96-100° C.

EXAMPLE 36 2-[4-(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)butyl]-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

C₂₇H₃₅N₅O₂S (493.7) MS: 494.3 [M+H]⁺.

EXAMPLE 37 2-(3-{[4-Methyl-5-thien-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-7-(piperidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=1.4 (m, 2H); 1.7 (m, 4H); 2.15 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 6H); 3.3 (t, 2H); 3.7 (m, 5H); 7.2 (d, 1H); 7.4 (s, 1H); 7.5 (m, 3H); 7.7 (s, 1H). C₂₄H₃₁N₅O₂S₃ (517.7) MS: 518.3 [M+H]⁺; Melting point: 192-195° C.

EXAMPLE 38 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-N-phenyl-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.6 (t, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.3 (t, 2H); 3.55 (s, 2H); 3.6 (s, 3H); 7.0 (m, 2H); 7.2 (m, 4H); 7.5 (m, 5H); 7.7 (m, 2H). C₂₇H₂₉N₅O₂S₂ (519.7) MS: 520.3 [M+H]⁺.

EXAMPLE 39 6-Chloro-2-{3-[(4-methyl-5-thien-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline

C₁₉H₂₁ClN₄S₂ (405); Melting point: 99-100° C.

EXAMPLE 40 7-[(Diethylammonio)methyl]-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline Dihydrochloride

C₂₆H₃₅N₅S.2HCl (522.6); Melting point: 75° C.

EXAMPLE 41 2-{3-[(4-Methyl-5-thien-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline Hydrochloride Preparation of the Starting Material

41A 7-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline

10.0 ml of concentrated sulfuric acid were slowly added dropwise to a solution of 1.77 g (6.2 mmol) of N-trifluoroacetyl-2-(4-trifluoromethylphenyl)ethylamine [prepared from 2-(4-trifluoromethylphenyl)ethylamine and trifluoroacetic anhydride at −5° C.] in 7.5 ml of glacial acetic acid, and, while cooling in ice, 2 ml of formalin solution were added dropwise. After 18 hours at room temperature, the reaction mixture was poured into 130 ml of ice-water and extracted with dichloromethane, and the combined organic phases were washed with sodium bicarbonate solution and then with water. After drying over sodium sulfate, filtration and evaporation, 1.7 g of 2-trifluoroacetyl-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline were isolated and were converted into 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline by heating under reflux in ethanol/3N HCl (1:1) and alkaline workup.

Yield: 1.0 g (4.7 mmol) 75% of theory. ¹H-NMR (CDCl₃): δ=2.0 (sbr, 1H); 2.9 (t, 2H); 3.2 (t, 2H); 4.0 (s, 2H); 7.2 (d, 1H); 7.3 (s, 1H); 7.4 (s, 1H).

41B 2-(3-Chloropropyl)-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline

0.95 g (4.7 mmol) of the compound described above was reacted with 1-bromo-3-chloropropane in the same way as described in Example 4B at room temperature, and purified by chromatography (silica gel, mobile phase dichloromethane with 2% methanol).

Yield: 0.9 g (3.2 mmol) 69% of theory. ¹H-NMR (CDCl₃): δ=2.0 (m, 2H); 2.65 (m, 2H); 2.75 (m, 2H); 2.9 (m, 2H); 3.65 (m, 4H); 7.2 (dd, 1H); 7.3 (d, 1H); 7.4 (dd, 1H).

41C Preparation of the Final Product

0.45 g (1.6 mmol) of 2-(3-chloropropyl)-7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline, 0.36 g (1.6 mmol) of 3-mercapto-4-methyl-5-thien-3-yl-4H-1,2,4-triazole and 40 mg of lithium hydroxide were stirred in 6 ml of DMF at 100° C. for 4 hours. Workup entailed pouring into ice/water, extraction with methyl tert-butyl ether, drying over sodium sulfate and purification after filtration and evaporation by column chromatography (silica gel, mobile phase dichloromethane with 3-5% methanol).

Yield: 0.3 g (0.7 mmol) 42% of theory. ¹H-NMR (CDCl₃): δ=2.1 (m, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 3.0 (m, 2H); 3.35 (t, 2H); 3.7 (m, 5H); 7.1 (d, 1H); 7.2 (s, 1H); 7.3 (d, 1H); 7.5 (m, 2H); 7.7 (s, 1H); [free base].

The title compound was obtained by treatment with ethereal HCl C₂₀H₂₁F₃N₄S₂.HCl (475); Melting point: 192-194° C.

EXAMPLE 42 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-8-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline Hydrochloride Preparation of the Starting Materials

42A 6/8-Trifluoromethyl-1,2,3,4-tetrahydroisoquinoline

5.3 g (18.6 mmol) of N-trifluoroacetyl-2-(3-trifluoromethyl-phenyl)ethylamine [prepared from 2-(3-trifluoromethylphenyl)ethylamine and trifluoroacetic anhydride at −5° C.] and 0.9 g (29 mmol) of paraformaldehyde were added to a mixture of 22 ml of glacial acetic acid and 30 ml of concentrated sulfuric acid. After 18 hours at room temperature, the reaction mixture was poured into 350 ml of ice-water and extracted with ethyl acetate, and the combined organic phases were washed with sodium bicarbonate solution and then with water. After drying over sodium sulfate, filtration and evaporation, 5.4 g of a mixture of 2-trifluoroacetyl-6- and -8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline were isolated. The protective group was eliminated by heating in ethanol/3N HCl (1:1) under reflux. The two isomers were separated after workup and purification by chromatography (silica gel, mobile phase dichloromethane with 2-4% methanol):

F1 1.2 g (5.7 mmol) 32% of theory of 8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline ¹H-NMR (CDCl₃): δ=1.9 (sbr, 1H); 2.8 (t, 2H); 3.1 (t, 2H); 4.2 (s, 2H); 7.2 (m, 2H); 7.5 (d, 1H).

F2 1.4 g (6.8 mmol) 38% of theory of 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline ¹H-NMR (CDCl₃): δ=1.8 sbr, 1H); 2.8 (t, 2H); 3.1 (t, 2H); 4.0 (s, 2H); 7.1 (d, 1H); 7.4 (m, 2H).

42 B 2-(3-Chloropropyl)-8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline

2-(3-Chloropropyl)-8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline was obtained in 73% yield by reacting 42-A F1 with bromochloropropane in a manner analogous to the description in Example 4C.

¹H-NMR (CDCl₃): δ=2.0 (q, 2H); 2.7-2.8 (m, 4H); 3.0 (t, 2H); 3.6 (t, 2H); 3.8 (s, 2H); 7.2-7.3 (m, 2H); 7.4 (d, 1H).

42C Preparation of the Final Compound

Reaction of 0.7 g (3.0 mmol) of 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole with 0.83 g (3.0 mmol) of 2-(3-chloropropyl)-8-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline [42B1] in 10 ml of DMF in the presence of 70 mg of lithium hydroxide at 100° C. afforded, after workup as described under 4D, 0.84 g (1.9 mmol) of the final compound.

Yield: 0.84 g (1.9 mmol) 65% of theory ¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.6-2.7 (m, 4H); 2.9 (t, 2H); 3.4 (t, 2H); 3.6 (s, 3H); 3.8 (s, 2H); 7.1 (t, 1H); 7.25 (d, 1H); 7.4 (d, 1H), 7.5 (m, 3H); 7.6 (m, 2H).

The title compound was obtained by treatment with ethereal HCl. C₂₂H₂₃F₃N₄S.HCl (469); Melting point: 118° C.

EXAMPLE 43 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline Hydrochloride Preparation of the Starting Materials

43 B2 2-(3-Chloropropyl)-6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline

2-(3-Chloropropyl)-6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline was obtained in 96% yield by reacting 6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline [42AF2] (obtained as described in 42A) with bromochloropropane in a manner analogous to that described for 4C.

¹H-NMR (CDCl₃): δ=2.0 (m, 2H); 2.6-2.8 (m, 4H); 2.9 (t, 2H); 3.6 (m, 4H); 7.1 (d, 1H); 7.4 (m, 2H).

43C Preparation of the Final Compound

Reaction of 0.7 g (3.0 mmol) of 3-mercapto-4-methyl-5-phenyl-1,2,4(4H)-triazole with 0.83 g (3.0 mmol) of 2-(3-chloropropyl)-6-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline in 10 ml of DMF in the presence of 70 mg of lithium hydroxide at 100° C. afforded, after workup as described under 4D, 0.75 g (1.7 mmol) of the final compound.

Yield: 0.75 g (1.7 mmol) 58% of theory; ¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.6 (t, 2H); 2.7 (t, 2H); 2.9 (t, 2H); 3.3 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 7.1 (d, 1H); 7.3 (m, 2H); 7.5 (m, 3H); 7.7 (m, 2H); [free base].

The title compound was obtained by treatment with ethereal HCl C₂₂H₂₃F₃N₄S.HCl (469); Melting point: 200-202° C.

EXAMPLE 44 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline Hydrochloride

C₂₂H₂₃F₃N₄S.HCl (469); Melting point: 205-207° C.

EXAMPLE 45 2-{3-[(4-Methyl-5-(thien-3-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(4-methylpiperazin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.2 (s, 3H); 2.4 (m, 4H); 2.7 (t, 2H); 2.8 (t, 2H); 2.9 (t, 2H); 3.0 (m, 4H); 3.3 (t, 2H); 3.6 (m, 5H); 7.2 (d, 2H); 7.45 (m, 4H); 7.7 (m, 1H). C₂₄H₃₂N₆O₂S₃ (538.8).

EXAMPLE 46 2-{3-[(4-Methyl-5-(phenyl)-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(4-methylpiperazin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.2 (s, 3H); 2.5 (m, 4H); 2.7 (t, 2H); 2.8 (t, 2H); 2.9-3.0 (m, 6H); 3.3 (t, 2H); 3.6 (s, 3H); 3.7 (s, 2H); 7.2 (d, 1H); 7.5 (m, 5H); 7.6 (m, 2H). C₂₆H₃₄N₆O₂S₃ (564.8).

EXAMPLE 47 2-{3-[(4-Methyl-5-(thien-3-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(1,2,3,4-tetrahydroisoquinolin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃): δ=2.1 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 2.9 (t, 2H); 3.2-3.3 (m, 4H); 3.6 (m, 2H); 3.7 (m, 5H); 4.2 (m, 2H); 7.1 (m, 4H); 7.2 (d, 1H); 7.4-7.6 (m, 4H); 7.7 (m, 1H). C₂₈H₃₁N₅O₂S₃ (565).

EXAMPLE 48 2-{3-[(4-Methyl-5-(pyrid-3-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(1,2,3,4-tetrahydroisoquinolin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

¹H-NMR (CDCl₃) δ=2.1 (q, 2H); 2.7 (t, 2H); 2.8 (t, 2H); 2.9 (m, 4H); 3.3 (m, 4H); 3.6 (s, 3H); 3.7 (s, 2H); 4.2 (s, 2H); 7.0-7.2 (m, 5H); 7.2 (m, 1H); 7.4-7.6 (m, 3H); 8.0 (m, 1H); 8.7 (m, 1H); 8.9 (m, 1H). C₂₉H₃₂N₆O₂S₂ (558).

EXAMPLE 49 7-[(3,3-Dimethylpiperidin-1-yl)sulfonyl]-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline

C₂₈H₃₇N₅O₂S₂ (539.8); Melting point: 75-76° C.

EXAMPLE 50 2-{3-[(4-Cyclopropyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-[(3,3-dimethylpiperidin-1-yl)sulfonyl]-1,2,3,4-tetrahydroisoquinoline

C₃₀H₃₉N₅O₂S₂ (558).

EXAMPLE 51 2-[(4-{[(4-Methyl-5-(1-methyl-1H-pyrrol-3-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]methyl}cyclohexyl)methyl]-7-nitro-1,2,3,4-tetrahydroisoquinoline

C₂₆H₃₁N₅O₂S (477.6); Melting point: 160° C.

EXAMPLE 52 2-{(E)-4-[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]but-2-enyl}-7-nitro-1,2,3,4-tetrahydroisoquinoline

C₂₁H₂₂N₆O₂S (422) MS: 423 [M+H]⁺.

EXAMPLE 53 2-[(4-{[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-methyl}cyclohexyl)methyl]-1,2,3,4-tetrahydroisoquinolin-7-carbonitrile

C₂₇H₃₁N₅S (457.6); Melting point: 156-158° C.

EXAMPLE 54 1-(2-{3-[(4-Methyl-5-(3-cyano)phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)ethanone Hydrochloride

C₂₄H₂₅N₅OS×HCl (468); Melting point: 185° C.

EXAMPLE 55 7-Nitro-2-[(4-{[(4-methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]-methyl}cyclo-hexyl)methyl]-1,2,3,4-tetrahydroisoquinoline

C₂₆H₃₁N₆O₂S (477.6); Melting point: 160° C.

EXAMPLE 56 1-{2-[3-({4-Methyl-5-phenyl]-4H-1,2,4-triazol-3-yl}sulfanyl)-propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}ethanone Hydrochloride

C₂₃H₂₇N₄OS×HCl (443); Melting point: 165° C.

EXAMPLE 57 7,8-Dichloro-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline

C₂₁H₂₂ClN₄S (399); Melting point: 72-75° C.

EXAMPLE 58 1-{2-[3-({5-(2,4-Dinitrophenyl)-4-methyl]-4H-1,2,4-triazol-3-yl}-sulfanyl)propyl]-1,2,3,4-tetrahydroisoquinolin-7-yl}ethanone Hydrochloride

C₂₃H₂₅N₆O₅S×HCl (500.6); Melting point: 193° C.

EXAMPLE 59 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(octahydroisoquinolin-2(1H)-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

C₃₀H₃₉N₅O₂S₂ (565.8) MS: 567 [M+H]⁺.

EXAMPLE 60 2-{3-[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(octahydroisoquinolin-2(1H)-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

C₂₉H₃₈N₆O₂S₂ (566.8) MS: 568 [M+H]⁺.

EXAMPLE 61 2-{3-[(4-Cyclopropyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

C₂₉H₃₇N₅O₂S₂ (551.8) MS: 552 [M]⁺.

EXAMPLE 62 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

C₂₅H₃₁N₅O₂S₂ (497.7).

EXAMPLE 63 2-{3-[(4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline

C₂₇H₃₅N₅O₂S₂ (525.7).

EXAMPLE 64 7-Chlor-2-(3-{[4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}-but-2-en-yl)-1,2,3,4-tetrahydroisoquinoline

C₂₁H₂₃ClN₄S (399); Melting point: 72-75° C.

EXAMPLE 65 2-(3-{[4-Methyl-5-methylamino-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-7-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline EXAMPLE 66 N,4-Dimethyl-5-{[3-(7-(piperidin-1-ylsulfonyl)-3,4-dihydroisoquinolin-2(1H)-yl)propyl]sulfanyl}-4H-1,2,4-triazol-3-amine EXAMPLE 67 7-tert-Butyl-2-(3-{[4-methyl-5-(4-methyl-1,3-thiazol-5-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline EXAMPLE 68 2-{3-[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(azepan-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline EXAMPLE 69 7-({4-[2-tert-Butyl-6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}sulfonyl)-2-{3-[(4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl)-sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline EXAMPLE 70 8-Brom-2-(3-{[5-cyclohexyl-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}but-2-en-yl)-1,2,3,4-tetrahydroisoquinoline EXAMPLE 71 4-Methyl-5-phenyl-N-[4-(7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl]-4H-1,2,4-triazole-3-carboxamide EXAMPLE 72 6-Methyl-2-(3-{[4-methyl-5-(1-methyl-1H-pyrrol-3-yl)-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline EXAMPLE 73 7-Cyano-2-[(2-{[(4-Methyl-5-pyridin-3-yl-4H-1,2,4-triazol-3-yl)-sulfanyl]-methyl}-cyclopropyl)methyl]-1,2,3,4-tetrahydroisoquinoline EXAMPLE 74 1-(2-{3-[(4-Methyl-5-(3-methoxy)phenyl-4H-1,2,4-triazol-3-yl)-oxy]propyl}-1,2,3,4-tetrahydroisoquinolin-7-yl)ethanone EXAMPLE 75 4-(7-(Pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline-2-yl)butyl-4-methyl-5-phenyl-4H-1,2,4-triazole-3-carboxylate EXAMPLE 76 2-[2-({[5-(N-Methyl)pyrrol-2-yl)-4-methyl-4H-1,2,4-triazol-3-yl]-sulfanyl}methyl)prop-2-enyl]-1,2,3,4-tetrahydroisoquinolin-7-carboxamide EXAMPLE 77 2-{3-[(4-Cyclopropyl-5-(4-methylsulfonyl)phenyl-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-7-(pyrrolidin-1-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline EXAMPLE 78 6-tert-Butyl-2-(3-{[5-(2,4-dinitrophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]sulfanyl}propyl)-1,2,3,4-tetrahydroisoquinoline EXAMPLE 79 N-[2-(8-{[5-(Dimethylamino)-4-butyl-4H-1,2,4-triazol-3-yl]sulfanyl}octyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]methansulfonamide EXAMPLE 80 2-{3-[(4-Methyl-5-pyrazin-2-yl-4H-1,2,4-triazol-3-yl)sulfanyl]-propyl}-7-(octahydroisoquinolin-2(1H)-ylsulfonyl)-1,2,3,4-tetrahydroisoquinoline EXAMPLE 81 7-Cyano-2-{3-[(4-methyl-5-(2-methyloxazol-4-yl)-4H-1,2,4-triazol-3-yl)sulfanyl]propyl}-1,2,3,4-tetrahydroisoquinoline EXAMPLE 82 2-{6-[(5-(2,5-Dimethylfuran-3-yl)-4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]hexyl}-7-trifluormethansulfonyloxy-1,2,3,4-tetrahydroisoquinoline EXAMPLE 83 2-[2-({[4-methyl-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}methyl)-prop-2-enyl]-7-nitro-1,2,3,4-tetrahydroisoquinoline Hydrochloride

C₂₂H₂₃N₅O₂S×HCl (460); Melting point: 146-150° C.

EXAMPLE 84 N-[2-(3-{[4-Methyl-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}-propyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]methansulfonamide

C₂₂H₂₇N₅O₂S₂×HCl (494.1); Melting point: 90° C.

The following compounds can be prepared in an analogous way in principle:

TABLE 1

Ex. R¹ R² A R⁶ R⁷ R⁸ 85 Me Ethoxycarbonyl S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- 8-methyl nyl) 86 Me N,N-Dimethyla- S—CH₂—CH═CH—CH₂— 6-methyl 7-cyano mino- 87 Et tert.Butyl (CH₂)₄— 7-cyano 88 Butyl Methylsulfanyl (CH₂)₄— 6-fluoro 89 cycProp Methyl S—(CH₂)₃— 6-chloro 7-chloro 90 Me 2,5-Di-methyl-fu- S—CH₂—CH═CH—CH₂— 7-(piperidin-1-yl-sulfo- ranyl-3- nyl) 91 Me 3-Thienyl COO—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 92 Me Phenyl- (CH₂)₄— 7-(3,3-dimethyl-piperi- din-1-yl-sulfonyl) 93 Me 2,4-Dimethoxyphe- S—(CH₂)₃— 7-methansulfonamid nyl 94 Me Amino- S—CH₂—C(═CH₂)—CH₂ 7-(piperidin-1-yl-sulfo- nyl) 95 Prop Phenyl S—CH₂—C(CH₃)═CH—CH₂— 8-trifluoromethyl 96 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 97 Me 3-Benzthienyl- S—(CH₂)₆— 7-(pyrolidin-1-yl-sulfo- nyl) 98 Me Phenyl- S—(CH₂)₇— 7-(pyrolidin-1-yl-sulfo- nyl) 99 Me Phenyl CONH—(CH₂)₄— 7-(piperidin-1-yl-sulfo- nyl) 100 Me 2-Pyrazinyl- S—(CH₂)₃— 7-trifluoromethyl 101 Phenyl Methyl (CH₂)₄— 7-(morpholin-1-yl-sulfo- nyl) 102 Me Tetrazolyl- S—(CH₂)₃— 7-methoxy 103 Et 4-Methylthia- S—(CH₂)₃— 7-methylsulfonyl zol-5-yl 104 Et 3-Jod-phenyl S—(CH₂)₃— 7-methansulfonamid 105 Et 4-Methylphenyl S—CH₂—C(═CH₂)—CH₂ 7-(piperidin-1-yl-sulfo- nyl) 106 Me N-Methyl-2-Pyrro- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) lyl- 107 Me 4-Methylthia- S—CH₂—C(═CH₂)—CH₂ 7-(pyrrolidin-1-yl-sulfo- zol-5-yl nyl) 108 Me 2,5-Di-methyl-fu- S—(CH₂)₃— 7-phenylsulfonyl ranyl-3- 109 Me 2-Me-4-Oxazolyl- (CH₂)₂—CH(CH₃)—CH₂—CH₂— 7-(morpholin-1-yl-sulfo- nyl) 110 Me Phenyl- S—(CH₂)₇— 7-(pyrolidin-1-yl-sulfo- nyl) 111 Hexyl 3-Pyridyl- S—(CH₂)₃— 6-chloro 7-chloro 112 Me 3-Cyano-phenyl S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 113 Me 2-Pyrazinyl- CO—(CH₂)₃— 7-(morpholin-1-yl-sulfo- nyl) 114 Prop Phenyl S—(CH₂)₄— 7-(morpholin-1-yl-sulfo- nyl) 115 Me 3-Metoxyphenyl (CH₂)₄— 6-triflourmethyl 116 Me 3-Pyrrolyl S—(CH₂)₃— 7-nitro 117 Et 3-Pyridyl S—(CH₂)₇— 6-methyl 7-cyano 118 Me 4-Methylthia- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- zol-5-yl nyl) 119 Me Phenyl CONH—(CH₂)₄— 7-cyano 120 Et 2,5-Di-methyl-fu- S—(CH₂)₃— 7-nitro ranyl-3- 121 Et N-Methyl-2-Pyrro- S—(CH₂)₃— 7-nitro lyl- 122 Prop Phenyl- S—(CH₂)₃— 6-methyl 7-(aze- pan-1-yl- sulfonyl) 123 Et N-Propyl-tetrazo- S—(CH₂)₃— 7-cyano lyl- 124 Me 3-Thienyl S—(CH₂)₃— 7-methylsulfonyl 125 Me 4-Methoxyphenyl S—(CH₂)₃— 4-methoxy 126 Me Tetrazolyl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 127 Me 4-Methylthia- S—CH₂-cycHex-CH₂— 7-phenylsulfonyl zol-5-yl CH₂— 128 Me 2-Chloro-phenyl CO—(CH₂)₃— 7-trifluoromethoxy 129 Et Phenyl- S—(CH₂)₃— 6-CH₂—CH₂—CH₂—CH₂-7 130 Et 4-Methoxyphenyl (CH₂)₂—CH(CH₃)—CH₂—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 131 Et 4-Methylthia- S—CH₂—C(═CH₂)—CH₂ 7-(azepan-1-yl-sulfonyl) zol-5-yl 132 Me 2-Me-4-Oxazolyl- S—(CH₂)₆— 7-nitro 133 Me 5-Methyl imida- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- zol-4-yl- nyl) 134 Me 3-Jod-phenyl S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 135 Me Phenylmethyl S—CH₂—CH═CH—CH₂— 7-(azepan-1-yl-sulfonyl) 136 Et Phenyl- S—(CH₂)₃— 6-CH(CH₃)CH₂—N(CH₃)-7 137 Et 3-Thienyl S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 138 Me 3-Jod-phenyl S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 139 Et Phenyl S—(CH₂)₃— 8-trifluoromethyl 140 Me Phenyl CONH—(CH₂)₅— 8-triflouromethyl 141 Me Phenyl- S—CH₂—CH═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 142 Me Cyclohexyl- S—(CH₂)₃— 7-nitro 143 iProp 3-Pyridyl S—(CH₂)₇— 7-chloro 8-chloro 144 Me Amino- S—(CH₂)₃— 7-cyano 145 Me 2-Aminothia- S—(CH₂)₃— 7-cyano zol-4yl- 146 Me 3-Pyrrolyl S—CH₂-cycProp-CH₂— 6-triflourmethyl 147 cycProp Phenyl- S—(CH₂)₃— 6-CH₂—CH₂—CH₂—CH₂-7 148 Me 2-Pyrazinyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 149 Me Cyclohexyl- S—(CH₂)₃— 7-cyano 150 Me 5-Methyl imida- (CH₂)₂—CH(CH₃)—CH₂—CH₂— tert-Butyl zol-4-yl- 151 Me Methylamino- S—(CH₂)₃— 7-cyano 152 Me 3-Benzthienyl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 153 Me Phenyl S—CH₂-cycHex-CH₂— 5-methoxy CH₂— 154 Me Pyridin-4-yl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 155 Prop Phenyl- S—CH₂—C(═CH₂)—CH₂ 7-(azepan-1-yl-sulfonyl) 156 Me 3-Pyridinyl S—(CH₂)₈— 7-CHF₂ 157 Me Tetrazolyl- (CH₂)₄— 7-(pyrolidin-1-yl-sulfo- nyl) 158 Me 4-Phenyl S—CH₂-cyc- 7-bromo Prop-(CH₂)₂— 159 Me 4-Methylphenyl COO—(CH₂)₄— 7-nitro 160 Et 3-Cyano-phenyl S—CH₂-cycHex-CH₂— 6-Methyl CH₂— 161 Et 2-Aminothia- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- zol-4yl- nyl) 162 Et Phenyl- (CH₂)₄— 7-(3,3-dimethyl-piperi- din-1-yl-sulfonyl) 163 Me 4-Methylthia- S—(CH₂)₃— 7-trifluoromethyl zol-5-yl 164 Me Oxadiazol-2-yl S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 165 Me 6-Chloro-biphe- S—(CH₂)₃— 7-methylsulfonyl nyl-2- 166 Et 3-Pyridinyl S—(CH₂)₈— 7-CHF₂ 167 Me Pyridin-3-yl- S—(CH₂)₃— 7-methylsulfonyl 168 Me Phenyl CONH—(CH₂)₄— 7-Phenylsulfonyl 169 Et 2-Me-4-Oxazolyl- S—(CH₂)₃— 8-trifluoromethyl 170 Me 5-Methyl imida- S—(CH₂)₃— 7-nitro zol-4-yl- 171 iProp Phenyl S—(CH₂)₃— 6-bromo 172 Prop 4-Imidazolyl- S—(CH₂)₃— 7-methoxy 173 Me Tetrazolyl- S—(CH₂)₃— 7-cyano 174 Et Phenyl CONH—(CH₂)₄— 6-chloro 7-chloro 175 Me 2-Pyrazinyl- S—(CH₂)₃— 7-methoxy 176 Prop Phenyl- S—(CH₂)₃— 6-methyl 7-nitro 177 Me 4-Jod-phenyl COO—(CH₂)₄— 7-cyano 178 iProp 4-Imidazolyl- S—CH₂—CH═CH—CH₂— 7-(azepan-1-yl-sulfonyl) 179 Et 4-Methylsulfonyl- S—(CH₂)₈— 7-(piperidin-1-yl-sulfo- phenyl nyl) 180 Butyl N-Propyl-tetrazo- S—(CH₂)₃— 7-cyano lyl- 181 Me 2-Me-4-Oxazolyl- S—CH₂—C(CH₃)═CH—CH₂— 7-(azepan-1-yl-sulfonyl) 182 Et 3-Pyrrolyl S—(CH₂)₃— 7-nitro 183 Me N-Propyl-tetrazo- S—CH₂—C(═CH₂)—CH₂ 7-(piperidin-1-yl-sulfo- lyl- nyl) 184 Me Propyl CO—(CH₂)₃— 5-methoxy 185 Me 2-Pyrazinyl- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 186 Me Oxadiazol-2-yl S—(CH₂)₃— 7-nitro 187 Prop 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 188 Hexyl Phenyl (CH₂)₄— 8-nitro 189 Prop Phenyl O—(CH₂)₃— 7-methoxy 190 Me 3-Pyridyl S—(CH₂)₇— 7-chloro 8-chloro 191 Et Oxadiazol-2-yl S—(CH₂)₃— 7-nitro 192 Et Phenyl- S—(CH₂)₃— 6-CH(CH₃)CH₂—NH-7 193 Me 3-Jod-phenyl S—(CH₂)₃— 7-methansulfonamid 194 Me Pyridin-4-yl- S—(CH₂)₃— 7-nitro 195 Me 4-Imidazolyl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 196 Me Phenyl (CH₂)₄— 8-nitro 197 Me 4-Methylphenyl S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 198 cycProp Phenyl S—(CH₂)₃— 7-Carboxamid 199 Me 3-Jod-phenyl O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 200 Me Cyclohexyl- S—(CH₂)₆— 7-(piperidin-1-yl-sulfo- nyl) 201 Me 3-Jod-phenyl S—CH₂—C(CH₃)═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 202 Me 3-Jod-phenyl S—(CH2)₃— 7-phenylsulfonyl 203 Butyl Pyridin-3-yl- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 204 cycProp 2,4-Dimethoxyphe- S—(CH₂)₃— 7-methansulfonamid nyl 205 Me N-Propyl-tetrazo- S—(CH₂)₃— 7-cyano lyl- 206 Et 4-Methoxyphenyl S—CH₂—CH═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 207 Et Phenyl- S—(CH₂)₃— 6-methyl 7-nitro 208 Et Phenyl- (CH₂)₂—CH(CH₃)—CH₂—CH₂— 6-methoxy 209 Me 3-Br-Pyri- S—(CH₂)₃— 7-nitro din-5-yl- 210 Me Methylamino- S—CH₂-cycHex-CH₂— 7-cyano CH₂— 211 Et tert.-Butyl CO—(CH₂)₃— 6-methoxy 212 Me Phenyl S—(CH₂)₃— 6-Fluoro 213 Me Phenylmethyl S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 214 iProp 4-Methoxyphenyl S—CH₂—CH═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 215 iProp 4-Cyano-phenyl S—CH₂—C(CH₃)═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 216 Me 3-Br-Pyri- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) din-5-yl- 217 Me Phenyl- S—(CH₂)₃— 6-CH₂—CH₂—CH₂—CH₂-7 218 Me 3-Cyano-phenyl S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 219 Me 3-Thienyl S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 220 Et Phenyl (CH₂)₄— 8-nitro 221 Me Amino S—(CH₂)₃— 7-nitro 222 Me 4-Methylsulfonyl- S—(CH₂)₈— 7-(piperidin-1-yl-sulfo- phenyl nyl) 223 Me 4-Methylsulfonyl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) phenyl 224 Me 4-Methylthia- S—(CH₂)₃— 7-methoxy zol-5-yl 225 Me 2-Me-4-oxazolyl- S—(CH₂)₃— 7-methylsulfonyl 226 Me 2,5-Di-methyl-fu- S—(CH₂)₃— 7-methoxy ranyl-3- 227 Me 3-Pyrrolyl S—(CH₂)₃— 7-cyano 228 Phenyl Cyano S—(CH₂)₃— 7-(pyrrolidin-1-yl-sulfo- nyl) 229 Me Tetrazolyl- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 230 Me Phenyl- S—(CH₂)₃— 6-methyl 7-cyano 231 Et Carboxamido S—(CH₂)₃— 7-cyano 232 Me Pyridin-3-yl- S—CH₂—C(CH₃)═CH—CH₂— 7-(azepan-1-yl-sulfonyl) 233 Et Phenyl S—(CH₂)₃— 6-bromo 234 Prop 2-Aminothia- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- zol-4yl- nyl) 235 Me Pyridin-4-yl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 236 Me 4-Methylthia- S—(CH₂)₃— 7-cyano zol-5-yl 237 cycProp Phenyl- S—(CH₂)₃— 6-CH₂—CH₂—CH₂-7 238 Me Pyridin-3-yl- S—CH₂—C(═CH₂)—CH₂ 7-(azepan-1-yl-sulfonyl) 239 Et 5-Methyl imida- S—(CH₂)₁₀— 7-(piperidin-1-yl-sulfo- zol-4-yl- nyl) 240 Me Methylamino S—(CH₂)₃— 7-nitro 241 Me Pyridin-4-yl- S—(CH₂)₆— 7-(piperidin-1-yl-sulfo- nyl) 242 Butyl Phenyl- S—(CH₂)₃— 6-methyl 7-cyano 243 Phenyl 3-Pyridyl- S—(CH₂)₆— 7-(piperidin-1-yl-sulfo- nyl) 244 Me Tetrazolyl- O—(CH₂)₃— 7-cyano 245 Hexyl 3-Jodphenyl- S—(CH₂)₃— 6-chloro 7-chloro 246 Me 4-Methylsulfonyl- S—CH₂-cycProp-CH₂— 7-cyano phenyl 247 Phenyl tert-Butyl S—(CH₂)₃— 7-(pyrrolidin-1-yl-sulfo- nyl) 248 Me tert.-Butyl (CH₂)₄— 6-methoxy 249 cycProp tert.-Butyl CO—(CH₂)₃— 6-methoxy 250 Me Amino- S—(CH₂)₃— 7-methylsulfonyl 251 Me Amino- S—(CH₂)₃— 6-methoxy 252 Et N-Methyl-2-Pyrro- S—(CH₂)8— 7-cyano lyl- 253 Me Methylamino- S—(CH₂)₃— 7-methoxy 254 Me Phenyl S—(CH₂)₃— 8-ethenyl 255 Et Phenyl S—CH₂-cycHex-CH₂— 7-trifluoromethoxy 256 Me N-Methyl-2-Pyrro- S—CH₂-cycProp-CH₂— 8-triflourmethyl lyl- 257 Prop 3-Jod-phenyl S—(CH₂)₃— 7-methansulfonamid 258 Me Methylamino- S—(CH₂)₃— 7-trifluoromethyl 259 Me Tetrazolyl- S—CH₂-cycHex-CH₂— 7-(morpholin-1-yl-sulfo- nyl) 260 Me Methylamino- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 261 Me N-Methyl-2-Pyrro- S—(CH₂)₃— 7-trifluoromethyl lyl- 262 Me 2-Aminothia- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) zol-4yl- 263 Me 3-Pyrrolyl S—(CH₂)₃— 7-methylsulfonyl 264 Me 4-Imidazolyl- S—CH₂—CH═CH—CH₂— 7-(azepan-1-yl-sulfonyl) 265 Me Propyl (CH₂)₄— 5-methoxy 266 Me Oxadiazol-2-yl S—(CH₂)₃— 6-trifluoromethyl 267 Me 4-Methylphenyl O—(CH₂)₃— 7-cyano 268 cycProp Phenyl (CH₂)₄— 8-nitro 269 Me 3-Br-Pyri- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- din-5-yl- nyl) 270 iProp Phenyl S—(CH₂)₃— 7-Acetyl 271 Me 4-Methylsulfonyl- S—(CH₂)₈— 7-(piperidin-1-yl-sulfo- phenyl nyl) 272 Me 3-Cyano-phenyl S—(CH₂)₃— 7-nitro 273 Me 4-Methylthia- S—(CH₂)₃— 7-methansulfonamid zol-5-yl 274 Me 3-Cyano-phenyl S—(CH₂)₃— 7-cyano 275 Me Oxadiazol-2-yl S—(CH₂)₃— 7-cyano 276 Me Phenyl- S—(CH₂)₇— 6-methyl 7-(pyroli- din-1-yl- sulfonyl) 277 Me Phenyl- CO—(CH₂)₃— 7-cyano 278 cycProp 4-Methoxyphenyl (CH₂)₄— 8-ethenyl 279 Me Phenyl S—CH₂—C(CH₃)═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 280 Me 6-Chloro-biphe- S—(CH₂)₃— 7-nitro nyl-2- 281 Me 4-Imidazolyl- S—(CH₂)₃— 8-trifluoromethyl 282 Me 3-Br-Pyri- S—(CH₂)₃— 7-cyano din-5-yl- 283 Pentyl 3-Pyridyl- S—(CH₂)₃— 6-chloro 7-chloro 284 Me Pyridin-3-yl- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 285 Me 3-Pyrrolyl S—(CH₂)₃— 7-methoxy 286 Me 2-Pyrazinyl- O—(CH₂)₃— 7-cyano 287 Et Phenyl- CO—(CH₂)₃— 7-cyano 288 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 289 Me 4-Methylsulfonyl- S—(CH₂)₃— 7-methylsulfonyl phenyl 290 Me Phenyl COO—(CH₂)₄— 7-(piperidin-1-yl-sulfo- nyl) 291 Me Oxadiazol-2-yl S—(CH₂)₃— 7-methylsulfonyl 292 Me 2-Aminothia- S—(CH₂)₃— 7-methoxy zol-4yl- 293 Me 4-Methylphenyl CONH—(CH₂)₄— 7-cyano 294 Me 3-Pyrrolyl S—CH₂—CH═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 295 Me 3-Cyano-phenyl S—(CH₂)₃— 7-methansulfonamid 296 Me 2-Pyrazinyl- S—CH₂-cyc- 7-(pyrolidin-1-yl-sulfo- Prop-(CH₂)₂— nyl) 297 Me Pyridin-3-yl- S—CH₂—C(═CH₂)—CH₂ 7-(piperidin-1-yl-sulfo- nyl) 298 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 299 Et 3-Br-Pyri- S—(CH₂)₃— 7-cyano din-5-yl- 300 Me 6-Chloro-biphe- S—(CH₂)₃— 7-trifluoromethyl nyl-2- 301 iProp Phenyl- S—(CH₂)₇— 6-methyl 7-(pyroli- din-1-yl- sulfonyl) 302 Me 3-Benzthienyl- S—(CH₂)₃— 7-nitro 303 Me Phenyl CONH—(CH₂)₄— 7-nitro 304 Me Cyclohexyl- S—(CH₂)₆— 7-(piperidin-1-yl-sulfo- nyl) 305 Me 3-Pyrrolyl S—CH₂—CH═CH—CH₂— 6-chloro 306 Et 2-Pyrazinyl- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 307 Me 4-Imidazolyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 308 Me 3-Pyridinyl S—(CH₂)₈— 7-CHF₂ 309 Me 3-Pyridyl COO—(CH₂)₃— 7-cyano 310 Me 3-Benzthienyl- S—(CH₂)₃— 7-cyano 311 Me 3-Pyrrolyl S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 312 Me 4-Methoxyphenyl (CH₂)₂—CH(CH₃)—CH₂—CH₂— 5-hydroxy 313 Me Amino- S—(CH₂)₃— 7-trifluoromethyl 314 Me 4-Methylthia- S—CH₂-cycProp-CH₂— 7-(piperidin-1-yl-sulfo- zol-5-yl nyl) 315 Me Tetrazolyl- S—(CH₂)₃— 7-phenylsulfonyl 316 Me Phenyl S—CH₂-cycHex-CH₂— 7-trifluoromethoxy 317 Phenyl 3-Thienyl S—(CH₂)₃— 7-nitro 318 Me Pyridin-3-yl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 319 Me 4-Methylphenyl S—CH₂—C(═CH₂)—CH₂ 7-(piperidin-1-yl-sulfo- nyl) 320 Prop 3-Benzthienyl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 321 Me 4-Methylthia- S—(CH₂)₃— 7-methylsulfonyl zol-5-yl 322 Me 4-Methoxyl-phenyl S—(CH₂)₈— 7-(piperidin-1-yl-sulfo- nyl) 323 Me Oxadiazol-2-yl S—(CH₂)₇— 7-azepan-1-yl-sulfonyl) 324 Me Methylamino- S—CH₂—cycProp-CH₂— 7-(piperidin-1-yl-sulfo- nyl) 325 Me 4-methoxyphenyl S—(CH₂)₃— 7-cyano 326 Butyl 2-Aminothia- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- zol-4yl- nyl) 327 iProp 3-Pyrrolyl S—CH₂—CH═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 328 Me Phenyl CONH—(CH₂)₄— 7-chloro 329 Butyl Phenyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- 8-chloro nyl) 330 Et 4-Imidazolyl- S—(CH₂)₃— 7-methoxy 331 Me Phenyl S—CH₂-cycProp-CH₂— 6-methoxy 332 Me 3-Furanyl S—CH₂-cycprop-CH₂— 7-(N-methylanilin-1-sulfo- nyl) 333 Me 2-Pyrazinyl- S—(CH₂)₃— 7-cyano 334 cycProp 2-Pyrazinyl- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 335 Et Phenyl S—(CH₂)₄— 7-(morpholin-1-yl-sulfo- nyl) 336 Me Phenyl- S—(CH₂)₃— 7-methylsulfonyl 337 Me 4-Methylphenyl O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 338 Butyl Phenyl S—(CH₂)₃— 7-acetyl 339 Et 4-Cyano-phenyl S—CH₂—C(CH₃)═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 340 Butyl Phenyl- S—(CH₂)₃— 6-Methyl 7-(pyroli- din-1-yl- sulfonyl) 341 Butyl Phenyl S—(CH₂)₃— 8-chloro 342 Et Pyridin-3-yl- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 343 Me 3-Thienyl S—(CH₂)₃— 7-methoxy 344 Me N-Methyl-2-Pyrro- S—CH₂-cycHex-CH₂— 5-methoxy lyl- CH₂— 345 Me 4-Imidazolyl- S—(CH₂)₃— 7-methoxy 346 cycProp Phenyl CONH—(CH₂)₅— 8-trifluoromethyl 347 Me 6-Chloro-biphe- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) nyl-2- 348 Et 3-Pyridyl S—(CH₂)₇— 7-chloro 8-chloro 349 Me 4-Methylsulfonyl- S—CH₂-cycHex-CH₂— 6-methoxy phenyl 350 Me Methylamino- S—(CH₂)₃— 7-methylsulfonyl 351 Et 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-methoxy 352 Et Phenyl- S—(CH₂)₃— 6-CH₂—CH₂—CH₂-7 353 Et Phenyl S—(CH₂)₄— 7-(pyrrolidin-1-yl-sulfo- nyl) 354 Butyl 2-Pyrazinyl- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 355 Me 4-Methoxyl-phenyl S—(CH₂)₈— 7-(piperidin-1-yl-sulfo- nyl) 356 Me Phenyl- (CH₂)₂—CH(CH₃)—CH₂—CH₂— 6-methoxy 357 Me 2-Aminothia- S—(CH₂)₃— 7-trifluoromethyl zol-4yl- 358 Prop Phenyl S—(CH₂)₃— 7-Acetyl 359 Me 4-Methylphenyl COO—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 360 Et 2-Me-4-Oxazolyl- (CH₂)₂—CH(CH₃)—CH₂—CH₂— 7-(morpholin-1-yl-sulfo- nyl) 361 Butyl Carboxamido S—(CH₂)₃— 7-cyano 362 Me Pyridin-4-yl- S—(CH₂)₃— 6-trifluoromethyl 363 Hexyl 3-Pyridyl- S—(CH₂)₃— 7-chloro 8-chloro 364 Me N-Propyl-tetrazo- S—(CH₂)₃— 7-methylsulfonyl lyl- 365 Et Phenyl- S—CH₂—C(═CH₂)—CH₂ 7-(azepan-1-yl-sulfonyl) 366 cycProp Phenyl- (CH₂)₄— 7-(3,3-dimethyl-piperi- din-1-yl-sulfonyl) 367 Me Phenyl CONH—(CH₂)₄— 6-chloro 7-chloro 368 Et 4-Imidazolyl- S—CH₂—CH═CH—CH₂— 7-(azepan-1-yl-sulfonyl) 369 Me Cyclohexyl- S—(CH₂)₃— 7-methoxy 370 Me 2-Pyrazinyl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 371 Prop 2-Me-4-Oxazolyl- S—(CH₂)₃— 8-trifluoromethyl 372 Me 2,4-Dimethoxy- S—CH₂—C(CH₃)═CH—CH₂— 7-(piperidin-1-yl-sulfo- phenyl nyl) 373 Me Cyclohexyl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 374 Me Pyridin-3-yl- S—(CH₂)₃— 7-methoxy 375 Me Phenyl- S—(CH₂)₃— 7-methoxy 376 Me 2-Pyrazinyl- S—CH₂-cycHex-CH₂— 7-(morpholin-1-yl-sulfo- nyl) 377 Me N-Propyl-tetrazo- S—(CH₂)₃— 7-nitro lyl- 378 Me Phenyl- (CH₂)₄— 8-triflourmethyl 379 Prop 4-Methoxyphenyl (CH₂)₄— 6-ethenyl 380 Me Phenyl- S—(CH₂)₇— 7-(pyrolidin-1-yl-sulfo- nyl) 381 iProp 4-Methylthia- S—(CH₂)₃— 7-methylsulfonyl zol-5-yl 382 iProp Phenyl- S—(CH₂)₇— 7-(piperidin-1-yl-sulfo- 8-chloro nyl) 383 iProp Phenyl S—(CH₂)₃— 7-carboxamid 384 Me Phenyl S—CH₂—C(CH₃)═CH—CH₂— 7-trifluoromethyl 385 Et Phenyl CONH—(CH₂)₅— 8-trifluoromethyl 386 iProp 3-Pyrrolyl S—(CH₂)₆— 7-cyano 387 Me Phenyl- S—(CH₂)₇— 7-(piperidin-1-yl-sulfo- 8-chloro nyl) 388 Et 3-Benzthienyl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 389 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-methoxy 390 Me 2-Aminothia- S—(CH₂)₃— 7-nitro zol-4yl- 391 Prop 3-Br-Pyri- S—(CH₂)₃— 7-cyano din-5-yl- 392 Me 3-Thienyl S—(CH₂)₃— 7-nitro 393 Et Phenyl CONH—(CH₂)₄— 7-chloro 394 Me 4-Methylthia- S—(CH₂)₃— 7-nitro zol-5-yl 395 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 396 Me 6-Chloro-biphe- S—(CH₂)₃— 7-cyano nyl-2- 397 Me Tetrazolyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 398 Me 3-Benzthienyl- S—(CH₂)₃— 7-methylsulfonyl 399 Me 3-Thienyl S—CH₂—CH═CH—CH₂— 7-(pyrrolidin-1-yl-sulfo- nyl) 400 Hexyl Phenyl- S—(CH₂)₃— 6-methyl 7-cyano 401 Me 3-Pyridyl S—(CH₂)₇— 6-methyl 7-cyano 402 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-methylsulfonyl 403 Me 3-Thienyl O—(CH₂)₃— 7-cyano 404 Prop Phenyl- S—(CH₂)₃— 6-methyl 7-(piperi- din-1-yl- sulfonyl) 405 Et 2,4-Dimethoxyphe- S—(CH₂)₃— 7-methansulfonamid nyl 406 Me Phenyl- S—(CH₂)₃— 7-trifluoromethyl 407 Me 4-Methoxyphenyl (CH₂)₂—CH(CH₃)— 7-(piperidin-1-yl-sulfo- CH₂—CH₂— nyl) 408 Me Phenyl S—CH₂-cyc- 5-methoxy Prop-(CH₂)₂— 409 Phenyl 3-Thienyl (CH₂)₄— 7-(piperidin-1-yl-sulfo- nyl) 410 Me 3-Thienyl S—(CH₂)₃— 7-methansulfonamid 411 Me Pyridin-3-yl- S—(CH₂)₃— 7-trifluoromethyl 412 Phenyl tert-Butyl O—(CH₂)₃— 7-(pyrrolidin-1-yl-sulfo- nyl) 413 Me 3-Pyrrolyl S—(CH₂)₃— 7-trifluoromethyl 414 Me N-Methyl-2-Pyrro- S—(CH₂)₃— 7-nitro lyl- 415 iProp Phenyl S—(CH₂)₃— 8-trifluoromethyl 416 Butyl 3-Thienyl S—(CH₂)₈— 7-(pyrrolidin-1-yl-sulfo- nyl) 417 Me Phenyl- S—CH₂—C(═CH₂)—CH₂ 7-(piperidin-1-yl-sulfo- nyl) 418 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-nitro 419 Me 2-Aminothia- S—(CH₂)₃— 7-phenylsulfonyl zol-4yl- 420 Me 4-Methylthia- O—(CH₂)₃— 7-cyano zol-5-yl 421 Me 4-Methylsulfonyl- S—(CH₂)₃— 7-trifluoromethyl phenyl 422 Me 4-methylsulfonyl- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- phenyl nyl) 423 Butyl 3-Pyridyl- S—(CH₂)₃— 7-chloro 8-chloro 424 Me Methylamino- S—CH₂—C(CH₃)═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 425 Me Carboxamido S—(CH₂)₃— 7-cyano 426 Me 4-Methoxyphenyl S—(CH₂)₃— 7-phenylsulfonyl 427 Et 3-Pyrrolyl S—CH₂—CH═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 428 Me 3-Cyano-phenyl S—(CH₂)₃— 7-trifluoromethyl 429 Me 5-Methyl imida- S—(CH₂)₃— 7-cyano zol-4-yl- 430 Prop N-Propyl-tetrazo- S—(CH₂)₃— 7-cyano lyl- 431 Me 2,5-Di-methyl-fu- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) ranyl-3- 432 Prop Pyridin-3-yl- S—CH₂—C(═CH₂)—CH₂ 7-(azepan-1-yl-sulfonyl) 433 Me 4-Methylsulfonyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- phenyl nyl) 434 Butyl Phenyl (CH₂)₄— 8-nitro 435 Me 4-Methylphenyl COO—(CH₂)₄— 7-(piperidin-1-yl-sulfo- nyl) 436 Me 3-Furanyl S—CH₂-cycHex-CH₂— 7-phenylsulfonyl CH₂— 437 Me 3-Jod-phenyl S—(CH₂)₃— 7-trifluoromethyl 438 Et 2-Pyrazinyl- O—(CH₂)₃— 8-ethenyl 439 Me 3-Benzthienyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 440 Me Cyclohexyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 441 Me Pyridin-3-yl- S—CH₂-cycHex-CH₂— 6-methoxy 442 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-nitro 443 Me 2-Pyrazinyl- (CH₂)₄— 7-(morpholin-1-yl-sulfo- nyl) 444 Prop 2-Pyrazinyl- S—(CH₂)₃— 8-ethenyl 445 Me 4-Methoxyphenyl S—(CH₂)₃— 7-trifluoromethyl 446 Me 4-Imidazolyl- S—(CH₂)₃— 7-methylsulfonyl 447 Me Phenyl- S—(CH₂)₇— 7-(pyrolidin-1-yl-sulfo- nyl) 448 Me Cyclohexyl- S—(CH₂)₃— 7-trifluoromethyl 449 Butyl Phenyl- (CH₂)₄— 7-(3,3-dimethyl-piperi- din-1-yl-sulfonyl) 450 Et Phenyl S—(CH₂)₃— 8-ethenyl 451 Me 4-Methoxyphenyl S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 452 iProp Phenyl S—(CH₂)₄— 7-(morpholin-1-yl-sulfo- nyl) 453 Me Cyano S—(CH₂)₈— 6,7-dimethoxy 454 Me 2-Aminothia- S—CH₂—CH═CH—CH₂— 7-(piperidin-1-yl-sulfo- zol-4yl- nyl) 455 Et Phenyl COO—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 456 Me 3-Cyano-phenyl S—(CH₂)₃— 7-methylsulfonyl 457 Me 2-Pyrazinyl- S—(CH₂)₃— 7-nitro 458 Me 3-Cyano-phenyl S—CH₂—C(═CH₂)—CH₂ 7-(piperidin-1-yl-sulfo- nyl) 459 cycProp N-Methyl-2-Pyrro- S—(CH₂)₈— 7-cyano lyl- 460 Me 4-Methoxyphenyl S—(CH₂)₃— 7-nitro 461 Me Oxadiazol-2-yl S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 462 Me Tetrazolyl- S—(CH₂)₇— 7-(piperidin-1-yl-sulfo- nyl) 463 Butyl Phenyl (CH₂)₄— 7-(pyrrolidin-1-yl-sulfo- nyl) 464 Prop 4-Methylphenyl S—CH₂—C(═CH₂)—CH₂ 7 (piperidin-1-yl-sulfo- nyl) 465 Me Phenyl- S—(CH₂)₃— 6-CH₂—CH₂—CH₂-7 466 Me N-Methyl-2-Pyrro- S—(CH₂)₃— 7-methylsulfonyl lyl- 467 Me 3-Thienyl S—(CH₂)₃— 7-trifluoromethyl 468 Et Cyano S—(CH₂)₈— 6-methoxy 7-methoxy 469 cycProp Phenyl- S—(CH₂)₃— 6-CH(CH₃)CH₂—NH-7 470 Me 3-Br-Pyri- S—(CH₂)₃— 7-methylsulfonyl din-5-yl- 471 Me Phenyl- S—(CH₂)₃— 6-CH(CH₃)CH₂—N(CH₃)-7 472 Et 4-Methoxyphenyl (CH₂)₄— 8-ethenyl 473 Me Tetrazolyl- S—(CH₂)₃— 7-trifluoromethyl 474 Me 6-Chloro-biphe- S—(CH₂)₃— 7-methoxy nyl-2- 475 Me 4-Pyridyl- (CH₂)₄— 7-(pyrolidin-1-yl-sulfo- nyl) 476 cycProp Phenyl CONH—(CH₂)₄— 6-chloro 7-chloro 477 Me 2-Me-4-Oxazolyl- S—(CH₂)₆— 7-nitro 478 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-methoxy 479 Me 4-Methoxyphenyl S—CH₂—CH═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 480 Me Cyano S—(CH₂)₈— 6-methoxy 7-methoxy 481 Me tert.-Butyl CO—(CH₂)₃ 6-methoxy 482 Et 3-Cyano-phenyl S—(CH₂)₃— 7-methansulfonamid 483 Prop Cyano S—(CH₂)₈— 6-methoxy 7-methoxy 484 Me 3-Pyrrolyl S—CH₂-cycHex-CH₂— 7-cyano CH₂— 485 Me Methylamino- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 486 Me 2,5-Di-methyl-fu- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- ranyl-3- nyl) 487 Me 2,5-Dimethyl-fu- S—(CH₂)₃— 7-nitro ranyl-3- 488 iProp 4-Methoxyphenyl (CH₂)₄— 8-ethenyl 489 Et Tetrazolyl- S—(CH₂)₃— 7-nitro 490 Me Phenyl COO—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 491 Me 4-Imidazolyl- S—(CH₂)₃— 7-nitro 492 Me 3-Thienyl O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 493 Et Phenyl S—CH₂—C(CH₃)═CH—CH₂— 8-trifluoromethyl 494 Me Pyridin-4-yl- S—(CH₂)₆— 7-nitro 495 Me N-Methyl-2-Pyrro- S—(CH₂)₃— 7-methansulfonamid lyl- 496 Et Phenyl- S—(CH₂)₃— 6-methyl 7-cyano 497 Prop 4-Methylthia- S—(CH₂)₃— 7-trifluoromethyl zol-5-yl 498 Me Phenyl O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 499 Me 4-Cyano-phenyl S—CH₂—C(CH₃)═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 500 Et Phenyl S—(CH₂)₃— 7-Carboxamid 501 Me N-Propyl-tetrazo- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- lyl- nyl) 502 Me Amino- S—(CH₂)₃— 7-(dimethylaminosulfonyl) 503 Me 2,4-Dimethoxy- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- phenyl nyl) 504 Me 3-Benzthienyl- CO-(CH₂)₃— 7-phenylsulfonyl 505 Me 4-Imidazolyl- S—(CH₂)₃— 7-cyano 506 Et Phenyl S—CH₂-cycHex-CH₂— 5-methoxy CH₂— 507 Et 3-Pyrrolyl S—(CH₂)₆— 7-cyano 508 Me 3-Pyrrolyl S—(CH₂)₃— 7-methansulfonamid 509 Me Tetrazolyl- S—(CH₂)₇— 7-(piperidin-1-yl-sulfo- nyl) 510 Me Tetrazolyl- S—(CH₂)₃— 7-methansulfonamid 511 Me 3-Thienyl COO—(CH₂)₄— 7-(piperidin-1-yl-sulfo- nyl) 512 Et 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 513 Me Pyridin-4-yl- S—(CH₂)₃— 7-methylsulfonyl 514 Butyl N-Methyl-2-Pyrro- S—(CH₂)₈— 7-cyano lyl- 515 Me Phenyl- S—(CH₂)₃— 6-CH(CH₃)CH₂—NH-7 516 Me Pyridin-4-yl- S—(CH₂)₃— 7-cyano 517 Me 3-Thienyl S—CH₂-cyc- 7-(3,3-dimethyl-piperi- Prop-(CH₂)₂— din-1-yl-sulfonyl) 518 Me 2,4-Dimethoxyphe- O—(CH₂)₃— 7-cyano nyl 519 Me 4-Methylsulfonyl- O—(CH₂)₃— 7-cyano phenyl 520 Me 4-Methylthia- S—CH₂—C(═CH₂)—CH₂ 7-(azepan-1-yl-sulfonyl) zol-5-yl 521 Me Amino- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 522 Prop N-Methyl-2-Pyrro- S—(CH₂)₈— 7-cyano lyl- 523 Me 5-Methyl imida- S—(CH₂)₃— 7-trifluoromethyl zol-4-yl- 524 Me Cyclohexyl- S—(CH₂)₃— 7-methylsulfonyl 525 Et Pyridin-3-yl- S—CH₂—C(═CH₂)—CH₂ 7-(azepan-1-yl-sulfonyl) 526 Prop Phenyl S—(CH₂)₃— 8-ethenyl 527 Me 5-Methyl imida- S—CH₂—C(CH₃)═CH—CH₂— 7-(pyrrolidin-1-yl-sulfo- zol-4-yl- nyl) 528 Me Tetrazolyl- S—CH₂-cycProp-CH₂— 6-methoxy 529 Me Phenyl- S—CH₂—C(═CH₂)—CH₂ 7-(azepan-1-yl-sulfonyl) 530 Me 6-Chloro-biphe- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl-2- nyl) 531 Et Phenyl- S—(CH₂)₇— 6-methyl 7-(pyroli- din-1-yl- sulfonyl) 532 Me Pyridin-3-yl- S—(CH₂)₃— 7-methansulfonamid 533 Me 2-Pyrazinyl- S—CH₂—C(═CH₂)—CH₂ 7-(piperidin-1-yl-sulfo- nyl) 534 Et 3-Jod-phenyl O—(CH₂)₃— 7-cyano 535 Me 3-Benzthienyl- S—(CH₂)₃— 6-methoxy 536 Me Oxadiazol-2-yl S—(CH₂)₃— 7-methoxy 537 Me 6-Chloro-biphe- S—CH₂—C(CH₃)═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl-2- nyl) 538 cycProp 4-Methylthia- S—CH₂—C(═CH₂)—CH₂ 7-(azepan-1-yl-sulfonyl) zol-5-yl 539 Me Pyridin-3-yl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 540 Et 4-Methylthia- S—(CH₂)₃— 7-trifluoromethyl zol-5-yl 541 Me 3-Pyrrolyl S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 542 Me 3-Pyridyl COO—(CH₂)₄— 7-(piperidin-1-yl-sulfo- nyl) 543 Prop Carboxamido S—(CH₂)₃— 7-cyano 544 Me 4-Jod-phenyl COO—(CH₂)₃— 7-cyano 545 Hexyl Phenyl- (CH₂)₄— 7-(3,3-dimethyl-piperi- din-1-yl-sulfonyl) 546 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-trifluoromethyl 547 Et Phenyl- S—(CH₂)₇— 7-(piperidin-1-yl-sulfo- 8-chloro nyl) 548 Prop Phenyl S—(CH₂)₄— 7-(pyrrolidin-1-yl-sulfo- nyl) 549 Me N-Propyl-tetrazo- S—(CH₂)₃— 7-methoxy lyl- 550 Me 2-Pyrazinyl- S—(CH₂)₃— 7-methylsulfonyl 551 Me Phenyl S—CH₂—C(CH₃)═CH—CH₂— 8-trifluoromethyl 552 Butyl tert.-Butyl CO—(CH₂)₃— 6-methoxy 553 Prop 5-Methyl imida- S—(CH₂)₁₀— 7-(piperidin-1-yl-sulfo- zol-4-yl- nyl) 554 Me 4-Jod-phenyl S—(CH₂)₃— 7-cyano 555 Me 5-Methyl imida- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) zol-4-yl- 556 Me 3-Benzthienyl- (CH₂)₄— 7-phenylsulfonyl 557 Me Pyridin-3-yl- O—(CH₂)₃— 7-cyano 558 Me Tetrazolyl- S—(CH₂)₃— 7-nitro 559 Me 3-Benzthienyl- S—(CH₂)₆— 7-(pyrolidin-1-yl-sulfo- nyl) 560 cycProp Phenyl S—(CH₂)₃— 7-Acetyl 561 iProp Phenyl S—(CH₂)₄— 7-(pyrrolidin-1-yl-sulfo- nyl) 562 Me Phenyl- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 563 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-cyano 564 Me 5-Methyl imida- S—(CH₂)₃— 7-methoxy zol-4-yl- 565 Prop Phenyl- S—(CH₂)₃— 6-CH(CH₃)CH₂—N(CH₃)-7 566 Me N-Propyl-tetrazo- S—(CH₂)₃— 7-trifluoromethyl lyl- 567 Me 2,5-Di-methyl-fu- S—(CH₂)₃— 7-trifluoromethyl ranyl-3- 568 Me Phenyl O—(CH₂)₃— 7-cyano 569 Me 4-Jod-phenyl S—(CH₂)₃— 7-nitro 570 Me N-Methyl-2-Pyrro- S—(CH₂)₃— 7-cyano lyl- 571 Prop 3-Pyridyl S—(CH₂)₇— 6-methyl 7-cyano 572 Me 2,5-Di-methyl-fu- S—(CH₂)₃— 7-cyano ranyl-3- 573 Me 2-Pyrazinyl- S—(CH₂)₃— 7-methansulfonamid 574 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 7-cyano 575 Et Phenyl O—(CH₂)₃— 7-cyano 576 Me Methylamino- S—(CH₂)₃— 7-methansulfonamid 577 Me 3-Thienyl S—(CH₂)₃— 7-cyano 578 Me 2-Chloro-phenyl (CH₂)₄— 7-trifluoromethoxy 579 Butyl 3-Pyrrolyl S—CH₂—CH═CH—CH₂— 7-(piperidin-1-yl-sulfo- nyl) 580 cycProp 3-Cyano-phenyl S—(CH₂)₃— 7-methansulfonamid 581 Me N-Propyl-tetrazo- S—(CH₂)₃— 7-(dimethylamino-sulfonyl) lyl- 582 Me 4-Methylphenyl COO—(CH₂)₄— 7-trifluoromethyl 583 Me 5-Methyl imida- S—(CH₂)₃— 7-methylsulfonyl zol-4-yl- 584 Me 3-Br-Pyri- S—(CH₂)₃— 7-methoxy din-5-yl- 585 Me 3-Thienyl S—CH₂-cycHex-CH₂— 7-trifluoromethoxy 586 Me Pyridin-3-yl- S—(CH₂)₃— 7-nitro 587 Et 3-Thienyl COO—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 588 Prop 3-Thienyl S—(CH₂)₃— 7-(dimethylaminosulfonyl) 589 Butyl 3-Br-Pyri- S—(CH₂)₃— 7-cyano din-5-yl- 590 Me Pyridin-3-yl- S—(CH₂)₃— 7-cyano 591 Et 3-Cyano-phenyl S—(CH₂)₃— 7-nitro 592 Prop Phenyl S—(CH₂)₁₀— 7-Carboxamid 593 Et 3-Furanyl S—CH₂-cycHex-CH₂— 7-phenylsulfonyl CH₂— 594 Me N-Methyl-2-Pyrro- S—(CH₂)₃— 7-methoxy lyl- 595 Me 3-Cyano-phenyl S—CH₂-cycHex-CH₂— 6-Methyl CH₂— 596 Me 4-Methylsulfonyl- S—(CH₂)₃— 7-methansulfonamid phenyl 597 Me 2-Aminothia- S—(CH₂)₃— 7-(piperidin-1-yl-sulfo- zol-4yl- nyl) 598 Prop Phenyl S—(CH₂)₃— 6-bromo 599 Prop 4-Methylthia- S—(CH₂)₃— 7-methylsulfonyl zol-5-yl 600 Me 2,4-Dimethoxyphe- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl nyl) 601 Et Pyridin-4-yl- S—(CH₂)₃— 7-nitro 602 Me N-Methyl-2-Pyrro- S—CH₂—C(CH₃)═CH—CH₂— 7-(piperidin-1-yl-sulfo- lyl- nyl) 603 Me 3-Br-Pyri- S—(CH₂)₆— 7-(piperidin-1-yl-sulfo- din-5-yl- nyl) 604 iProp Phenyl- S—(CH₂)₃— 6-methyl 7-cyano 605 Et 2-Pyrazinyl- CO—(CH₂)₃— 7-(morpholin-1-yl-sulfo- nyl) 606 Me Phenyl- S—(CH₂)₃— 6-methyl 7-nitro 607 Butyl 4-Methylthia- S—CH₂—C(═CH₂)—CH₂ 7-(azepan-1-yl-sulfonyl) zol-5-yl 608 Me 4-Methoxyphenyl S—(CH₂)₃— 7-(dimethylamino-sulfonyl) 609 Me 3-Br-Pyri- S—(CH₂)₆— 7-(piperidin-1-yl-sulfo- din-5-yl- nyl) 610 Me Pyridin-4-yl- S—(CH₂)₃— 7-methoxy 611 cycProp Pyridin-3-yl- O—(CH₂)₃— 7-(piperidin-1-yl-sulfo- nyl) 612 Me 3-Br-Pyri- S—(CH₂)₃— 7-trifluoromethyl din-5-yl- 613 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 8-trifluoromethyl 614 Prop Phenyl S—(CH₂)₃— 8-trifluoromethyl 615 Me 3-Benzthienyl- S—(CH₂)₃— 7-trifluoromethyl 616 Et Phenyl S—(CH₂)₃— 7-acetyl 617 Me Pyridin-3-yl- S—CH₂-cycProp-CH₂— 7-(pyrolidin-1-yl-sulfo- nyl) 618 Me Oxadiazol-2-yl S—(CH₂)₇— 7-(piperidin-1-yl-sulfo- nyl) 619 Phenyl 3-Thienyl S—(CH₂)₃— 7-cyano 620 Me 3-Jod-phenyl O—(CH₂)₃— 7-cyano 621 Me Phenyl CONH—(CH₂)₄— 6-methoxy 8-methyl 622 Me 3-Thienyl S—(CH₂)₃— 6-CH(CH₃)CH₂—NH-7 5-methyl 623 Me 3-Thienyl S—(CH₂)₃— 6-CH₂—CH₂—CH₂—CH₂-7 8-bromo 624 Me 4-Pyridyl S—(CH₂)₃— 6-CH₂—CH₂—CH₂-7 8-ethe- nyl 625 Me 3-Pyridyl- S—(CH₂)₃— 5-methoxy 7-chloro 8-chloro 626 Me 3-Phenyl- O—(CH₂)₃— 6-chloro 7-chloro 8-methyl

If no meaning is given, R⁷ and R⁸ are hydrogen.

Here and in the following tables is:

Me=methyl

Et=ethyl

cycProp=cyclopropyl

Prop=n−propyl

iProp=isopropyl

cycHex=cyclohexyl

The following compounds can be prepared in an analogous way in principle:

TABLE 2

Ex. R¹ R² A R⁶ 627 Me Phenyl CONH—(CH₂)4— 5-nitro 628 Butyl Methylamino S—(CH₂)₃— 5-fluoro 629 Me Oxadiazol-2-yl S—(CH₂)₇— 5-(piperidin-1-yl-sulfonyl) 630 Me Tetrazolyl- S—(CH₂)₇— 5-(piperidin-1-yl-sulfonyl) 631 Me 3-Cyano-phenyl S—(CH₂)₃— 5-fluoro 632 Et 3-Thienyl S—(CH₂)₃— 5-methoxy 633 Me Carboxamid S—CH₂—C(CH₃)═CH—CH₂— 5-methoxy 634 Butyl Cyclohexyl- S—CH₂—cycProp-(CH2)₂— 5-chloro 635 Me 3-Pyrrolyl S—(CH₂)₃— 5-nitro 636 Me 2-Pyrazinyl- S—(CH₂)₃— 5-nitro 637 Pentyl tert.-Butyl CO—(CH₂)₃— 6-methoxy 638 Me Pyridin-3-yl- CO—(CH₂)₃— 5-fluoro 639 Me 4-Jod-phenyl S—(CH₂)₃— 5-fluoro 640 Me 4-Methylsulfonyl-phenyl S—(CH₂)₈— 5-(piperidin-1-yl-sulfonyl) 641 iProp N-Propyl-tetrazolyl- S—(CH₂)₃— 5-fluoro 642 cycProp tert.-Butyl CO—(CH₂)₃— 6-methoxy 643 Me 2-Aminothiazol-4yl- S—(CH₂)₃— 5-fluoro 644 cycProp 4-Methylsulfonyl-phenyl S—(CH₂)₈— 5-(piperidin-1-yl-sulfonyl) 645 Me Pyridin-3-yl- S—CH₂—CH═CH—CH₂— 5-methoxy 646 Me N-Propyl-tetrazolyl- S—CH₂—CH═CH—CH₂— 5-nitro 647 cycProp Carboxamido S—(CH₂)₃— 5-fluoro 648 Me N-Methyl-2-Pyrrolyl- S—(CH₂)₃— 5-nitro 649 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 5-nitro 650 Me Pyridin-4-yl- S—(CH₂)₃— 5-nitro 651 Me 3-Br-Pyridin-5-yl- S—CH₂—CH═CH—CH₂— 5-methoxy 652 Me Phenyl- S—(CH₂)₃— 5-fluoro 653 Me 4-Jod-phenyl S—(CH₂)₃— 5-methoxy 654 Me 3-Pyrrolyl S—(CH₂)₃— 5-methoxy 655 Me Phenyl- S—CH₂—CH═CH—CH₂— 5-(piperidin-1-yl-sulfonyl) 656 Me 3-Cyano-phenyl S—(CH₂)₃— 5-methoxy 657 Me N-Methyl-2-Pyrrolyl- S—CH₂-cycProp-(CH2)₂— 5-methoxy 658 Me Phenyl O—(CH₂)₃— 5-cyano 659 Pentyl Cyclohexyl- S—(CH₂)₃— 5-chloro 660 Me 3-Benzthienyl- S—CH₂-cycProp-(CH₂)₂— 5-fluoro 661 Pentyl Carboxamido S—(CH₂)₃— 5-chloro 662 Et 5-Methyl imidazol-4-yl- S—CH₂—CH═CH—CH₂— 5-methoxy 663 iProp Cyclohexyl- S—(CH₂)₃— 5-fluoro 664 Me 3-Benzthienyl- S—(CH₂)₃— 5-nitro 665 Butyl Cyclohexyl- S—CH₂—cycProp-(CH₂)₂— 5-methoxy 666 Me 4-Methoxyphenyl S—(CH₂)₃— 5-methoxy 667 Prop N-Propyl-tetrazolyl- S—CH₂—CH═CH—CH₂— 5-fluoro 668 Pentyl Phenyl CONH—(CH₂)₄— 5-cyano 669 Me Phenyl- CO—(CH₂)₃— 5-methoxy 670 Prop Cyclohexyl- S—(CH₂)₃— 5-fluoro 671 Butyl Methylamino S—(CH₂)₃— 5-methoxy 672 Me 4-Methylthiazol-5-yl S—(CH₂)₃— 5-cyano 673 cycProp N-Propyl-tetrazolyl- S—CH₂—CH═CH—CH₂— 5-nitro 674 cycProp Propyl CO—(CH₂)₃— 5-methoxy 675 Me Oxadiazol-2-yl S—CH₂—CH═CH—CH₂— 5-nitro 676 Me 3-Pyridyl S—(CH₂)₇— 5-chloro 677 Me 5-Methyl imidazol-4-yl- S—(CH₂)₃— 5-fluoro 678 Me 5-Methyl imidazol-4-yl- S—CH₂—C(CH₃)═CH—CH₂— 5-(pyrrolidin-1-yl-sulfonyl) 679 Me 3-Pyrrolyl S—(CH₂)₃— 5-fluoro 680 Me Cyclohexyl- O-(CH₂)₃— 5-nitro 681 Me Methylamino- S—CH₂—C(CH₃)═CH—CH₂— 5-(piperidin-1-yl-sulfonyl) 682 iProp 6-Chloro-biphenyl-2- S—(CH₂)₃— 5-fluoro 683 Me 3-Cyano-phenyl S—(CH₂)₃— 5-nitro 684 Pentyl N-Propyl-tetrazolyl- S—CH₂—CH═CH—CH₂— 5-chloro 685 Me Phenyl CONH—(CH₂)₄— 5-cyano 686 cycProp Phenyl COO—(CH₂)₃— 5-(piperidin-1-yl-sulfonyl) 687 Me Amino S—(CH₂)₃— 5-nitro 688 Me Phenyl CONH—(CH₂)₄— 5-chloro 689 Me 2-Pyrazinyl- S—(CH₂)₃— 5-fluoro 690 Me 4-Jod-phenyl S—CH₂—CH═CH—CH₂— 5-nitro 691 Me 2-Pyrazinyl- S—CH₂-cycProp-(CH₂)₂— 5-(pyrolidin-1-yl-sulfonyl) 692 Me Pyridin-4-yl- S—(CH₂)₃— 5-methoxy 693 Pentyl 4-Methylsulfonyl-phenyl S—(CH₂)₈— 5-(piperidin-1-yl-sulfonyl) 694 Pentyl N-Methyl-2-Pyrrolyl- S—(CH₂)₃— 5-chloro 695 cycProp Phenyl O—(CH₂)₃— 5-cyano 696 Me 4-Imidazolyl- S—(CH₂)₃— 5-nitro 697 Me 3-Pyrrolyl S—CH₂—CH═CH—CH₂— 6-chloro 698 Me Oxadiazol-2-yl (CH2)₂—CH(CH₃)—CH₂—CH₂— 5-fluoro 699 Me 6-Chloro-biphenyl-2- S—(CH₂)₃— 5-nitro 700 Butyl 4-Methoxyphenyl S—(CH₂)₃— 5-methoxy 701 Me 3-Br-Pyridin-5-yl- S—(CH₂)₃— 5-nitro 702 Prop N-Propyl-tetrazolyl- S—CH₂—CH═CH—CH₂— 5-chloro 703 Me 5-Methyl imidazol-4-yl- (CH₂)₂—CH(CH₃)—CH₂—CH₂— tert-Butyl 704 Pentyl Carboxamido S—(CH₂)₃— 5-fluoro 705 Me 2-Pyrazinyl- S—(CH₂)₃— 5-methoxy 706 Pentyl Phenyl- CO—(CH₂)₃— 6-methoxy 707 Me 4-Imidazolyl- S—(CH₂)₃— 5-methoxy 708 Me Phenyl- CO—(CH₂)₃— 6-methoxy 709 Me Tetrazolyl- S—CH₂—C(═CH₂)—CH₂ 5-nitro 710 cycProp N-Methyl-2-Pyrrolyl- S—(CH₂)₃— 5-chloro 711 cycProp Cyclohexyl- S—(CH₂)₃— 5-nitro 712 cycProp Carboxamido S—(CH₂)₃— 5-chloro 713 iProp 2,5-Di-methyl-furanyl-3- S—(CH₂)₃— 5-fluoro 714 Me Amino S—CH₂-cycProp-(CH₂)₂— 5-fluoro 715 Me 3-Thienyl (CH₂)₂—CH(CH₃)—CH₂—CH₂— 5-fluoro 716 Me 3-Thienyl O—(CH₂)₃— 5-nitro 717 Me tert.-Butyl CO—(CH₂)₃— 6-methoxy 718 Me Amino S—(CH₂)₃— 5-methoxy 719 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 5-fluoro 720 Et Tetrazolyl- S—CH₂—C(CH₃)═CH—CH₂— 5-methoxy 721 Prop Carboxamido S—(CH₂)₃— 5-chloro 722 Et 4-Methylthiazol-5-yl S—(CH₂)₃— 5-methoxy 723 Me 4-Imidazolyl- S—(CH₂)₃— 5-fluoro 724 Me 4-Methylthiazol-5-yl S—(CH₂)₃— 5-fluoro 725 Et 2-Me-4-Oxazolyl- S—(CH₂)₃— 5-methoxy 726 Butyl 4-Methoxyphenyl S—(CH₂)₃— 5-fluoro 727 Me 2,5-Di-methyl-furanyl-3- S—(CH₂)₃— 5-methoxy 728 Me 3-Br-Pyridin-5-yl- S—(CH₂)₃— 5-fluoro 729 Pentyl N-Methyl-2-Pyrrolyl- S—(CH₂)₃— 5-fluoro 730 cycProp N-Methyl-2-Pyrrolyl- S—(CH₂)₃— 5-nitro 731 Prop Cyclohexyl- S—(CH₂)₃— 5-chloro 732 cycProp 3-Pyridyl S—(CH₂)₇— 5-chloro 733 cycProp Cyclohexyl- S—(CH₂)₃— 5-chloro 734 Me N-Propyl-tetrazolyl- S—(CH₂)₃— 5-methoxy 735 Me Methylamino S—(CH₂)₃— 5-nitro 736 Me Pyridin-3-yl- S—(CH₂)₃— 5-nitro 737 Me 2-Aminothiazol-4yl- S—(CH₂)₃— 5-nitro 738 Et Oxadiazol-2-yl S—(CH₂)₃— 5-methoxy 739 Me 3-Cyano-phenyl S—CH₂—C(═CH₂)—CH₂ 5-(piperidin-1-yl-sulfonyl) 740 cycProp Phenyl- CO—(CH₂)₃— 6-methoxy 741 Me 2-Me-4-Oxazolyl- (CH₂)₂—CH(CH₃)—CH₂—CH₂— 5-(morpholin-1-yl-sulfonyl) 742 Et 2-Aminothiazol-4yl- S—CH₂—CH═CH—CH₂— 5-methoxy 743 Me 2,5-Di-methyl-furanyl-3- S—(CH₂)₃— 5-nitro 744 Me Phenyl COO—(CH₂)₃— 5-(piperidin-1-yl-sulfonyl) 745 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 5-fluoro 746 iProp Pyridin-4-yl- S—(CH₂)₃— 5-fluoro 747 Me Methylamino S—CH₂-cycProp-(CH₂)₂— 5-methoxy 748 Me 5-Methyl imidazol-4-yl- S—(CH₂)₃— 5-nitro 749 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 5-cyano 750 cycProp Carboxamido S—(CH₂)₃— 5-cyano 751 Me Tetrazolyl- S—(CH₂)₃— 5-fluoro 752 Pentyl Cyclohexyl- S—(CH₂)₃— 5-fluoro 753 Prop N-Methyl-2-Pyrrolyl- S—(CH₂)₃— 5-chloro 754 Me N-Methyl-2-Pyrrolyl- S—(CH₂)₃— 5-fluoro 755 cycProp N-Propyl-tetrazolyl- S—CH₂—CH═CH—CH₂— 5,6-dichloro 756 Pentyl Propyl CO—(CH₂)₃— 5-methoxy 757 Me 4-Methoxyphenyl S—(CH₂)₃— 5-nitro 758 Me Propyl CO—(CH₂)₃— 5-methoxy 759 Me 2-Me-4-Oxazolyl- S—(CH₂)₃— 5-methoxy 760 cycProp Phenyl CONH—(CH₂)₄— 5-cyano 761 Me Carboxamido S—(CH₂)₃— 5-cyano 762 Et tert.Butyl S—CH₂-cycProp-(CH₂)₂— 5-methoxy 763 cycProp N-Methyl-2-Pyrrolyl- S—(CH₂)₃— 5-fluoro

Examples of Pharmaceutical Administration Forms

A) Tablets

Tablets of the following composition were pressed on a tabletting machine in the customary manner

40 mg of the substance from Example 1

120 mg of corn starch

13.5 mg of gelatin

45 mg of lactose

2.25 mg of Aerosil® (chemically pure silicic acid in a submicroscopically fine dispersion)

6.75 mg of potato starch (as a 6% paste)

B) Sugar-coated tablets

20 mg of the substance from Example 3

60 mg of core composition

70 mg of sugar-coating composition

The core composition consists of 9 parts of corn starch, 3 parts of lactose and 1 part of vinylpyrrolidone-vinyl acetate 60:40 copolymer. The sugar-coating composition consists of 5 parts of cane sugar, 2 parts of corn starch, 2 parts of calcium carbonate and 1 part of talc. The sugar-coated tablets which have been prepared in this way are then provided with an enteric coating.

Biological Investigations—Receptor Binding Studies

D₃ binding test

Cloned human D₃-receptor-expressing CCL 1,3 mouse fibroblasts, obtainable from Res. Biochemicals Internat. One Strathmore Rd., Natick, Mass. 01760-2418 USA, were used for the binding studies.

Cell Preparation

The D₃-expressing cells were multiplied in RPMI-1640 containing 10% fetal calf serum (GIBCO No. 041-32400 N); 100 U of penicillin/ml and 0.2% streptomycin (GIBO BRL, Gaithersburg, Md., USA). After 48 h, the cells were washed with PBS and incubated for 5 min with 0.05% trypsin-containing PBS. After that, the solution was neutralized with medium and the cells were collected by centrifuging at 300 g. In order to lyse the cells, the pellet was washed briefly with lysis buffer (5 mM Tris-HCl, pH 7.4, containing 10% glycerol) and after that incubated, at 4° C. for 30 min, at a concentration of 10⁷ cells/ml of lysis buffer. The cells were centrifuged at 200 g for 10 min and the pellet was stored in liquid nitrogen.

Binding Tests

For the D₃-receptor binding test, the membranes were suspended in incubation buffer (50 mM Tris-HCl, pH 7.4, containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, 2 mM MgCl₂, 10 μM quinolinol, 0.1% ascorbic acid and 0.1% BSA), at a concentration of approx. 10⁶ cells/250 μl of test mixture, and incubated at 30° C. with 0.1 nM ¹²⁵iodosulpiride in the presence and absence of the test substance. The nonspecific binding was determined using 10⁻⁶ M spiperone.

After 60 min, the free radioligand and the bound radioligand were separated by filtering through GF/B glass fiber filters (Whatman, England) on a Skatron cell harvester (Skatron, Lier, Norway), and the filters were washed with ice-cold Tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The K_(i) values were determined by means of nonlinear regression analysis using the LIGAND program.

2) D₂ binding test

Cell Culture

HEK-293 cells possessing stably expressed human dopamine D2A receptors were cultured in RPMI 1640 containing Glutamix I™ and 25 mM HEPES containing 10% fetal calf serum albumin. All the media contained 100 units of penicillin per mol and 100 μg/ml of streptomycin/ml. The cells were maintained at 37° C. in a moist atmosphere containing 5% CO₂.

The cells were prepared for the binding studies by trypsinizing them (0.05% solution of trypsin) at room temperature for 3-5 minutes. After that, the cells were centrifuged at 250 g for 10 minutes and treated with lysis buffer (5 mM Tris-HCl, 10% glycerol, pH 7.4) at 4° C. for 30 minutes. After centrifuging at 250 g for 10 minutes, the residue was stored at −20° C. until used.

Receptor Binding Tests

Low affinity state dopamine D₂ receptor using ¹²⁵I-spiperone (81 TBq/mmol, Du Pont de Nemours, Dreieich)

The test mixtures (1 ml) consisted of 1×10⁵ cells in incubation buffer (50 mM Tris, 120 mM NaCl, 5 mM KCl, 2 mM MgCl₂ and 2 mM CaCl₂, pH 7.4 with HCl) and 0.1 mM ¹²⁵I-spiperone (total binding) or additionally 1 μM haloperidol (nonspecific binding) or test substance.

After the test mixtures had been incubated at 25° C. for 60 minutes, they were filtered through GM/B glass filters (Whatman, England) on a Skatron cell harvester (from Zinsser, Frankfurt), and the filters were washed with ice-cold 50 mM Tris-HCl buffer, pH 7.4. The radioactivity which had collected on the filters was quantified using a Packard 2200 CA liquid scintillation counter.

The results were evaluated as described in a).

The K_(i) values were determined by way of nonlinear regression analysis using the LIGAND program or by converting the IC₅₀ values using the Cheng and Prusoff formula.

In these tests, the compounds according to the invention exhibit very good affinities for the D₃ receptor (<1 μmolar, in particular <100 nmolar) and bond selectively to the D₃ receptor.

In table 3 pK_(i)(D₃) values (negative logarithm of the affinity constant for the D₃ receptor) and selectivity versus D₂ receptor (K_(i)(D₂)/K_(i)(D₃)) are given for the compounds of the examples 3, 4 and 7.

TABLE 3 Example pK_(i) (D₃) Selectivity 3 8,02 78 4 7,96 67 7 8,37 81 

We claim:
 1. A triazole compound of the formula I

where R¹ is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₃-C₆-cycloalkyl or phenyl; R² is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COOR³, CONR³R⁴, NR³R⁴, SO₂R³, SO₂NR³R⁴ or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from O, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COR³, NR³R⁴, NO₂, SO₂R³, SO₂NR³R⁴ and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C₁-C₆-alkyl, C₁-C₆-alkoxy, NR³R⁴, CN, CF₃, CHF₂ or halogen; R³ and R⁴ are, independently of each other, H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, or phenyl; A is C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z which is selected from O, S, CONR³, COO, CO, C₃-C₆-cycloalkyl and a double or triple bond; B is a radical of the following formula:

where X is CH₂ or CH₂CH₂; R⁶, R⁷ and R⁸ are, independently of each other, selected from H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, which may be substituted by amino, mono- or di-C₁-C₄-alkylamino; C₁-C₆-alkylthio, halogen or phenyl; OH, C₁-C₆-alkoxy, OCF₃, OSO₂CF₃, SH, C₁-C₆-alkylthio, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, NO₂, C(O)CH₃, CO₂R³, SO₂R³, SO₂NR³R⁴, where R³ and R⁴ have the abovementioned meanings and may also form together with the N atom to which they are bonded a saturated or unsaturated heterocycle with 5 to 7 ring atoms and 1 or 2 N heteroatoms, CONR³R⁴, NHSO₂R³, NR³R⁴, a 5- or 6-membered carbocyclic, aromatic or nonaromatic ring and a 5- or 6-membered heterocyclic, aromatic or nonaromatic ring with 1 or 2 heteroatoms which are selected, independently of each other, from O, N and S, with the carbocyclic or heterocyclic ring being able to have one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, phenyl, phenoxy, halogen, C₁-C₆-alkoxy, OH, NO₂, CF₃ and CHF₂, and with two of the substituents R⁶, R⁷ and R⁸ being able to form, together with the carbon atoms of the phenyl ring to which they are bonded, a phenyl, cyclopentyl or cyclohexyl ring which is fused to the phenyl ring, with the possibility for one or two of the CH or CH₂ groups in the fused ring being replaced by a nitrogen atom, an NH or an N—C₁-C₆ alkyl group; or a salt thereof with a physiologically tolerated acid.
 2. A compound as claimed in claim 1 of the formula I, where A is C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z which is selected from O, S, COO, CO, a double bond or triple bond and C₃-C₆-cycloalkyl.
 3. A compound as claimed in claim 1 of the formula I, where A is C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z which is selected from O, S, a double bond and cyclohexyl.
 4. A compound as claimed in claim 1 of the formula I, where R² is an aromatic radical which is unsubstituted or has one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, OH, C₁-C₆-alkoxy, phenyl, CN and halogen.
 5. A compound as claimed in claim 1 of the formula I, where R² is H, C₁-C₆-alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, pyridyl or pyrazinyl.
 6. A compound as claimed in claim 1 of the formula I, where R¹ is H, C₁-C₆-alkyl or C₃-C₆-cycloalkyl.
 7. A compound as claimed in claim 1 of the formula I, where R⁶, R⁷ and R⁸ are selected, independently of each other, from H, C₁-C₆-alkyl, OH, C₁-C₆-alkoxy, C₁-C₆-akylthio-C₁-C₆-alkyl, halogen, CN, C(O)CH₃, NO₂, SO₂R³, SO₂NR³R⁴ and CONR³R⁴.
 8. A compound as claimed in claim 1 of the formula I, where R¹ is H, C₁-C₆-alkyl or phenyl, R² is H, C₁-C₆-alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, thiazolyl or pyrazinyl, A is —SC₃—C₁₀-alkylene which may comprise a double bond, and R⁶, R⁷ and R⁸ are selected from H, C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, SO₂NR³R⁴, CN, C(O)CH₃, NO₂, CF₃, CONR³R⁴, CHF₂, OSO₂CF₃, OCF₃ and NHSO₂—C₁-C₆-alkyl.
 9. A pharmaceutical which comprises at least one compound as claimed in claim 1, optionally together with physiologically acceptable excipients and/or adjuvants.
 10. A triazole compound of formula I

where R¹ is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₃-C₆-cycloalkyl or phenyl; R² is H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COOR³, CONR³R⁴, NR³R⁴, SO₂R³, SO₂NR³R⁴ or an aromatic radical which is selected from phenyl, naphthyl and a 5- or 6-membered heterocyclic radical having 1, 2, 3 or 4 heteroatoms which are selected, independently of each other, from O, N and S, with it being possible for the aromatic radical to have one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, C₁-C₆-alkoxy, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₆-cycloalkyl, halogen, CN, COR³, NR³R⁴, NO₂, SO₂R³, SO₂NR³R⁴ and phenyl which may be substituted by one or two radicals which are selected, independently of each other, from C₁-C₆-alkyl, C₁-C₆-alkoxy, NR³R⁴, CN, CF₃, CHF₂ or halogen; R³ and R⁴ are, independently of each other, H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, halogen or phenyl, or phenyl; A is C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z which is selected from O, S, CONR³, COO, CO, C₃-C₆-cycloalkyl and a double or triple bond; B is a radical of the following formula:

where X is CH₂CH₂; R⁶, R⁷ and R⁸ are, independently of each other, selected from H, C₁-C₆-alkyl, which may be substituted by OH, OC₁-C₆-alkyl, which may be substituted by amino, mono- or di-C₁-C₄-alkylamino; C₁-C₆-alkylthio, halogen or phenyl; OH, C₁-C₆-alkoxy, OCF₃, OSO₂CF₃, SH, C₁-C₆-alkylthio, C₂-C₆-alkenyl, C₂-C₆-alkynyl, halogen, CN, NO₂, C(O)CH₃, CO₂R³, SO₂R³, SO₂NR³R⁴, where R³ and R⁴ have the abovementioned meanings and may also form together with the N atom to which they are bonded a saturated or unsaturated heterocycle with 5 to 7 ring atoms and 1 or 2 N heteroatoms, CONR³R⁴, NHSO₂R³, NR³R⁴, a 5- or 6-membered carbocyclic, aromatic or nonaromatic ring and a 5- or 6-membered heterocyclic, aromatic or nonaromatic ring with 1 or 2 heteroatoms which are selected, independently of each other, from O, N and S, with the carbocyclic or heterocyclic ring being able to have one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, phenyl, phenoxy, halogen, C₁-C₆-alkoxy, OH, NO₂, CF₃ and CHF₂, and with two of the substituents R⁶, R⁷ and R⁸ being able to form, together with the carbon atoms of the phenyl ring to which they are bonded, a phenyl, cyclopentyl or cyclohexyl ring which is fused to the phenyl ring, with the possibility for one or two of the CH or CH₂ groups in the fused ring being replaced by a nitrogen atom, an NH or an N—C₁-C₆ alkyl group; or a salt thereof with a physiologically tolerated acid.
 11. The compound defined in claim 10, wherein A is C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z selected from the group consisting of O, S, COO, CO, a double bond, a triple bond and C₃-C₆-cycloalkyl.
 12. The compound defined in claim 10, wherein A is C₄-C₁₀-alkylene or C₃-C₁₀-alkylene which comprises at least one group Z selected from the group consisting of O, S, a double bond and cyclohexyl.
 13. The compound defined in claim 10, wherein R² is an aromatic radical which is unsubstituted or has one or two substituents which are selected, independently of each other, from C₁-C₆-alkyl, OH, C₁-C₆-alkoxy, phenyl, CN and halogen.
 14. The compound defined in claim 10, wherein R² is H, C₁-C₆-alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, pyridyl or pyrazinyl.
 15. The compound defined in claim 10, wherein R¹ is H, C₁-C₆-alkyl or C₃-C₆-cycloalkyl.
 16. The compound defined in claim 10, wherein R⁶, R⁷ and R⁸ are selected, independently of each other, from H, C₁-C₆-alkyl, OH, C₁-C₆-alkoxy, C₁-C₆-akylthio-C₁-C₆-alkyl, halogen, CN, C(O)CH₃, NO₂, SO₂R³, SO₂NR³R⁴ and CONR³R⁴.
 17. The compound defined in claim 10, wherein R¹ is H, C₁-C₆-alkyl or phenyl, R² is H, C₁-C₆-alkyl, phenyl, thienyl, furanyl, tetrazolyl, pyrrolyl, thiazolyl or pyrazinyl, A is —SC₃-C₁₀-alkylene which may comprise a double bond, and R⁶, R⁷ and R⁸ are selected from H, C₁-C₆-alkyl, C₁-C₆-alkoxy, halogen, SO₂NR³R⁴, CN, C(O)CH₃, NO₂, CF₃, CONR³R⁴, CHF₂, OSO₂CF₃, OCF₃ and NHSO₂—C₁-C₆-alkyl.
 18. A pharmaceutical which comprises at least one compound as defined in claim 10, optionally together with physiologically acceptable excipients and/or adjuvants. 